Journal of

J.Neurol. 216, 207--215 (1977)

Neurology © by Springer-Verlag 1977

Amyloid Neuropathy Due to Monoclonal Gammopathy A Case Report B. Neund6rfer t, J. G. Meyer l, and B. Volk 2 1Neurological Clinic Mannheim, Theodor-Kutzer-Ufer, D-6800 Mannheim, Federal Republic of Germany 2Neuropathologic Institute of the University Heidelberg, Berliner StraBe44, D-6900Heidelberg, Federal Republic of Germany

Summary. A case with peripheral neuropathy due to monoclonal gammopathy is reported. There was striking, dissociated symmetrical sensory loss and paresis, the legs being affected predominantly. The case is compared with the few reported cases of myelomatous neuropathy, and the clinical and histological findings are discussed in view of the pathogenesis. Key words: Monoclonal gammopathy - Myeloma - Peripheral neuropathy Amyloidosis - Malabsorption. Zusammenfassung. Es wird fiber den Fall einer Polyneuropathie bei monoclonaler Gammopathie berichtet. Das klinische Bild war gepr~igt von symmetrisch-paretischen Ausf~illen mit dissoziierten Empfindungsst6rungen. Histologisch fanden sich Amyloidablagerungen im peripheren Nerven. Der Fall wird mit den wenigen gleichgelagerten F~illen in der Literatur verglichen, und die sich daraus ergebenden Konsequenzen ftir die Oberlegungen zur Pathogenese werden diskutiert. Introduction The first description of peripheral neuropathy in the course of myeloma by Davison and Balser [18] was followed by numerous case reports [1, 3, 7, 10--13, 15--19, 21, 23--28, 30, 32--38, 40--42, 45, 47, 48] which drew attention to its frequency and its controversial pathophysiology. Histology showed a prominent axonal degeneration and a demyelination considered to be mainly consequential [1, 10, 18, 19, 28, 38, 41, 42]. In some cases [2, 10, 28, 33] there were also plasma cell nerve infiltrates. Systemic deposits of amyloid were found with myeloma in 15% [4]. Thus, infiltrates and amyloid were suggested to be related to neuropathy but only 4 cases with amyloid deposits in peripheral nerves have been published [11, 16, 25, 27]. We made the diagnosis of monoclonal gammopathy in a patient with severe chronic neuropathy based on clinical and histological evidence. Both are to be discussed in view of their diagnostic significance.

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Fig. 1. a Sural nerve with homogenous endoneurial deposits. Azure II-methylene blue stain, semi thin section. The deposits also show Congo red stain and red-green dichromism. A reduction of myelinated fibers is striking. × 800. b Electron micrograph from a showing the area marked by arrows in a. Amyloid deposits are predominant. Myelinated any nonmyelinated axons are absent. S = schwann cell. × 3400

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Fig. 2. a Sural nerve, electron micrograph, x 36000. Amyloid deposits (in the left upper part the higher magnification of × 70 000) which may be distinguished from collagens on cross (simple arrows) a n d longitudinal (double arrow) section, b Onion bulbs in the sural nerve. Electron micrograph × 18000. There are many collagens among the processes of the schwann cells

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Fig. 3. a Basement membrane (double arrow) surrounding a schwann cell with large deposits of fibrillary amyloid, x 36 000. b Section from a with higher magnification of 70 000 showing densly packed fibrillary amyloid between organelles (eR: endoplasmatic reticulum, Go: Golgi apparatus, Mi: mitochondria)

Case Report A man, aged 64, suffered from progressive numbness and weakness of both legs for 3 years. From the very beginning there was thermohypestesia, which he first noticed when taking a warm bath, loss of sexual potency and trophic skin lesions. An initial constipation was followed .by chronic diarrhea and heart burn. He lost weight and always felt tired and weak. Later he had pains and developed digitoplantar gangrene. Progressive worsening could not be stopped by vitamin, gymnastic or vasodilating therapy. The skin of the feet and legs developed blue and yellow spots and, later, ulcers. He also developed a steppage gait due to weakness and mild atrophy of the extensors and flexors of the feet and toes. The ankle jerks were lost but the knee jerks were not obviously reduced. The arms and hands showed no motor impairment, and tendon reflexes were normal. Analgesia was present up to both knees while sensation of touch was only slightly diminished in this region.

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542.03038 20 (;CO3,75

Fig. 4. Serum electrophoresis showing an elevated y-globulin of 28.1% (normal 9--20). Total protein 7.2g/100ml. Albumin 43.9%, a~-globulin 4.9%, a2-globulin 12.3%, fl-globulin 10.8%

Thermohypesthesia was similarly distributed and could also be found on the back of both hands. All deficits were strictly symmetrical. His ancestors were not affected, nor were his children. The families of his father and mother had been settled in the Mannheim area for more than two generations. Electromyography revealed denervation of the distal muscles of both feet. The tibial and peroneal muscles were also affected. Slight denervation was present in the right abductor of the thumb and that of the little finger as shown by excess of polyphasic potentials, fibrillations and by a reduced number of motor unit potentials under voluntary control. Conduction velocities were distinctly slowed: median nerve 42 m/sec (normal 50 m/see), ulnar nerve 44.8 m/see (normal 50 m/sec). No responses required for measurements could be elicited by peroneal or tibial nerve stimulation. Microscopic analysis: blood smear was normal, but in the bone marrow there was a striking increase of plasma cells, 10--20% being atypical, and small infiltrates. ATPase reaction was reduced. Gastrointestinal mucosa (mouth, stomach, jejunum and colon) showed no specific changes endoscopically or histologically. Sural nerve and muscle were stained using the trichrome method and that of KlueverBarrera, Bodian, hematoxylin and Congo red. Electron microscopic study was performed with a Zeiss EM 9 A after the tissue had been exposed to 3.5% buffered glutaris aldehyde and to a secondary fixation by 2% osmic acid. F o r contrast lead and uranyle acetate were used. In the gastrocnemius the muscle fibers were atrophic and elongated. There were also target and targetoid fibers in disseminated small groups which were considered to be a sign of neurogenic muscle fiber atrophy. Concomitant myopathy was manifest by centralized nuclei and fibers rounded off. There were nodular clods of amyloid deposits in the endoneurium of the sural nerve (Fig. 1 a). They showed Congo red stain and the tyical red-green dichromism. There was also a striking reduction of myelinated fibers. The electron micrograph revealed the nodular and annular shape of amyloid (Fig. 1 b) which was shown to be composed of fibrils prominent at higher magnification (Fig. 2a). They could also be seen in the cytoplasm of schwann cells (Fig. 3 a - - b ) . Onion bulbs are shown in Figure 2b. Laboratory findings: serum protein studies revealed an elevated gammaglobulin (Fig. 4) which could be specified as type G a m m a G / L a m b d a by immunoelectrophoresis. There was no sign of antibody deficiency. This pathological globulin could not be observed by urine electrophoresis. Bence-Jones proteins were absent, too. Cardiolipin and pallida reaction suggested autoinhibition. Blood sedimentation was 43/68, alkaline phosphatase was within normal range. Xylose excretion test was significantly reduced due to malabsorption (5%;

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normal 24--40%). the same was true for vitamin Bl2 without and with intrinsic factor (6.7 and 3.4% respectively; normal 10%). X-rays of spine and pelvis showed no distinct osteolytic defects. There were some questionable osteolytic bright spots only in the skull.

Comment

The findings reported represent a type of monoclonal gammopathy closely bordering multiple myeloma because of some infiltrates of plasma cells in bone marrow and a decrease of ATPase reaction [43]. Osteoporosis and distinct osteolytic defects typical for multiple myeloma, however, were absent. But skull X-rays showed some questionable bright spots. Despite some peculiar abnormalities the case reported here may be compared with those with myelomatous neuropathy [1, 3, 7, 10--13, 14--19, 21, 23--28, 30, 32--38, 40--42, 45, 47, 48]. The clinical syndrome of myelomatous neuropathy commonly presents symmetrical distal sensory motor deficits [27, 34, 37]. In some patients muscles may be affected more severely and prevail over sensory disturbances. Frequently, as in our case, there are also severe pains and paresthesias. Moreover, our patient developed a specific sensory loss. We found a regional dissociation with decreased sensation of pain and rather good preservation of touch. Both legs were almost completely anestetic distally. There was also a striking trophic disturbance of the lower legs and feet. In fact, the constellation of symptoms reported is not typical for myelomatous neuropathy but pathognomonic for hereditary amyloidosis [2, 5, 14, 37, 39]. Thus the clinical signs of this case were already suspected of being due to amyloidotic deposits in peripheral nerves. This was actually confirmed by histological examination. We think this therefore an example that clinical sensory testing may be sufficient for differential etiological diagnosis and morphological changes may be suspected if there is a dissociated sensory loss. There are only a few other causes for this disturbance [37]. Our patient was free from all of them. This case may be distinguished from hereditary amyloid neuropathy [2, 5, 14, 37, 39] just because there is no familial disposition. Moreover, with hereditary amyloidosis there has been no proof for paraproteins in serum or urine. In most cases of myelomatous neuropathy there was a striking axonal degeneration partially concomitant with segmental demyelination [1, 10, 18, 19, 28, 38, 41, 42, 47, 48], the latter probably being only a consequence [34]. Only one case, published by Mayo et al. [33], presented a prevailing demyelination. Plasma cell infiltrates [3, 10, 28, 33] and amyloid deposits [11, 16, 25, 27] were only exceptional and may be meaningless for pathogenesis of neuropathy in most cases. A specific antigen antibody reaction due to abnormal immunglobulins released by myelomatous cells may be assumed to initiate nerve damage [34]. This hypothesis may explain the fluorescence microscopic findings of Chazot et al. [12] of an abnormal monoclonal protein in peripheral nerves in cases of IgG myeloma. Thus the rare cases of amyloid deposits in peripheral nerves in the course of myeloma may be related to these findings because amyloid may be considered nothing other than a paraprotein produced by plasma cells.

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The histological findings on light and electron microscopy in our case correspond completely to those observed with cases of hereditary amyloidosis [9, 20, 29]. The nodular clods of amyloid in connective tissue of nerve fibers are quite the same. The fibers themselves have a striking mixture of axonal degeneration and demyelination. Bischoff [9] suggested the destruction of fibers to be due to amyloid pressing or even dissolving the basement membrane of schwann cells. A disturbed diffusion barrier between axis cylinder and surrounding tissue and secondary disturbances of metabolism may be consequential. As already stated above amyloidosis is only a rare cause for myelomatous neuropathy. Only 4 cases have been reported [11, 16, 25, 27]. In the case reported by Campbell and Halford I11] amyloid affected only the vasa nervorum but not the fibers directly. Similarly, in Waldenstr/Sm's disease neuropathy, concomitant with amyloid deposits, was observed in only a few cases [6, 8, 22, 31, 44]. Amyloid due to paraproteinemias has obviously only a small affinity for nerve tissue, being stored more often in other tissues such as cardiac muscle, intestinal submucosa and periarthrodial and vascular tissue which may be affected in about 15% [4]. Our patient developed malabsorption in the later course. Absorption tests were distinctly pathological [46]. Biopsy and histological examination of the small intestine, however, showed no amyloid because amyloid is typically present only in the deep layer of submucosa beyond reach of biopsy [43]. Malabsorption cannot be primarily responsible because the clinical features of a dissociated sensory loss are atypical for malabsorption neuropathy in any way [37]. The same is true for the histological findings which do not correspond to malabsorption but are typical for amyloid neuropathy.

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Amyloid neuropathy due to monoclonal gammopathy. A case report.

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