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Cryoglobulinemic neuropathy A pathological study.

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Cryoglobuhnemic Neuropathy:
A Pathological Study
J. M. Vallat, MD, R. Desproges-Gotteron, MD, M. J. Leboutet, MD,
A. Loubet, MD, N. Gualde, MD, and R. Treves, MD
A 53-year-old woman developed symmetrical polyneuropathy of the lower limbs a few months after she was found
to have myeloma with cryoglobulinemia. In musculocutaneous nerve biopsy material, electron microscopy showed
both axonal degeneration and demyelination. T h e most striking finding was the presence, i n the endoneurial space,
of numerous masses of closely packed tubular structures. These masses also were found in t h e walls of all the vasa
nervorum and within the lumen of some vessels. The morphological features and dimensions of the deposits within
nerve were identical to those of cryoprecipitates extracted from serum and examined with the electron microscope.
An example of myeloma neuropathy with cryoglobulin deposits within t h e endoneurial space has not been reported
Vallat JM, Desproges-Gotteson R, Leboutet MJ, et al: Cryoglobulinemic neuropathy: a pathological study.
Ann Neurol 8:179-185, 1980
Polyneuropathy, reported in 13% of cases of multiple myeloma [30], may dominate the clinical picture
and sometimes precedes detection of the illness by
months to years [141. T h e pathogenesis of myelomatous neuropathy is disputed. A m o n g postulated mechanisms are cellular infiltration of the
nerves [2, 211, amyloidosis [8, 131, subperineurial
immunoglobulin deposition [9], and cryoglobulinemia [20]. I n the patient w e report here, ultrastructural analysis verified the presence of the same
cryoglobulin ( G component) in t h e serum, endoneurial spaces, and lumens and walls of nerve capillaries.
The findings, which appear t o be unique, suggest that
cryoglobulin contributed to the peripheral nerve
damage in this patient.
Case Report
A 53-year-old woman was hospitalized in November,
1977, for weakness and diffuse pain. General examination
was normal, but a skeletal survey disclosed osteolytic lesions in both femurs, the pelvis, several vertebrae, and the
skull. The sedimentation rate was 140 mm per hour. Serum
electrophoresis showed a monoclonal peak in the gamma
globulin region. Total protein was 8.8 g d d l , albumin 2.94
mg/dl, and gamma globulin 3.54 mg/dl. Immunoelectrophoresis revealed a monoclonal IgG peak with a K chain.
Quantitative immunodiffusion showed: IgG, 2,600 mgldl
(normal, 600 to 1,200); IgA, 150 mg/dl (normal, 121 to
409); and IgM, 4 9 mgldl (normal, 50 to 110). The serum
formed a solid gel at 4°C that was reversed by warming to
37°C. The cryoprecipitate protein was analyzed and
From the Departments of Neurology, Rheumatic Diseases, Pathology, and Hematology, Centre Hospitalier Universitaire
Dupuytren, Limoges, France.
characterized as pure IgG by the Ouchterlony doublediffusion method. Bence Jones protein was present in the
urine. A bone marrow aspirate showed increased numbers
of plasmocytes, often arranged in islets.
A diagnosis of myeloma with a unique cryoprecipitate
protein was made, and combination chemotherapy was instituted on a six-week schedule according to the following
regimen: BCNU, 41) mg daily for two days; cyclophosphamide, 300 mg daily; melphalan, 3 mg daily for seven
days; and prednisone, 30 mg daily for three weeks. In addition, 1.8 mg of vincristine was administered to the patient
every three weeks for a total of three courses.
In March, 1978, the patient complained of sensorimotor
difficulties affecting the extremities. Within a few weeks
she had developed a severe polyneuropathy affecting all
four limbs with bone sensitivity. Her gait was unsteady;
deep tendon reflexes were absent. The general clinical examination was normal. The cerebrospinal fluid (CSF) contained 0.2 lymphocyte/ml, CSF protein was 50 mg/dl. A
rectal mucosal biopsy revealed no amyloid infiltrate.
M a t e r i a l s and Methods
Biopsies were taken from the terminal portion of the musculocutaneous nerve of the leg and from the peroneus brevis muscle. Paraffin sections and'sections for electron microscopy were prepared using standard techniques. For
electron microscopy, small pieces of nerve were immediately fixed in 2.5% glutaraldehyde for 1 hour and then
washed in phosphate buffer for 12 hours. Posthation was
in 1% osmium tetroxide for 1 hour. After dehydration in
ethanol, blocks were embedded in epon or in araldite. Sections were stained with lead citrate and uranyl acetate and
were examined with a Zeiss 9 electron microscope.
Received Apr 9, 1979, and in revised form N o v 26. Accepted for
publication Dec 2, 1979.
Address reprint requests to J. M. Vallat, MD, Department of Neurology, C. H. U. Dupuytren, 87 031 Limoges Cedex, France.
@ 1979 by J. M. Vallat
Semithin transverse and longitudinal sections were stained
with toluidine blue. Immunofluorescent analysis was done
on paraffin sections using anti-IgA, anti-IgG, and anti-IgM
After removal of supernatant, the serum cryoprecipitate
was fixed for electron microscopic examination as just described.
O n light microscopy the nerve biopsy showed no abnormal deposition o r cellular infiltration of the endoneurium. O n semithin sections we observed a
marked decrease in myelinated fibers.
O n electron microscopic examination many fibers
exhibited severe thinning o r absence of myelin
sheaths, but the most striking abnormality was the
presence throughout the endoneurium of randomly
distributed deposits, some in contact with Schwann
cells (Figs 1-3). We found the same deposits in large
numbers in the walls of nearly all capillaries examined (Figs 4, 5), on either side of the basement membrane and in relation to pericytes. Some membranebound deposits were seen within the cytoplasm of
endothelial cells (Fig 5). O n one occasion we encountered a deposit inside the lumen of a capillary.
At high magnification we found that all deposits were
tubular in appearance. These tubules were arranged
in a distinctive pattern, forming fingerprint-like images. The external diameter of the tubules was 320
180 Annals of Neurology Vol 8 No 2
August 1980
Fig 1. High-power view of musculocutaneous nerve. Besides the
paucity of myelinated and unmyelinatedfibers, note the presence of numerous dense deposits in the endoneurial space (arrows). (Uranyl acetatellead citrate; ~ 1 , 9 5 0 . )
A, internal diameter 150 A, and wall thickness 70 A.
Although we identified a few apparently normal
fibroblasts in the endoneurium, we were unable to
find any plasmocytes. Immunofluorescent study of a
nerve section failed to reveal staining.
In the muscle biopsy, no tubular deposits were
seen either in o r between muscle fibers.
The electron microscopic appearance of the cryoprotein was striking. With low-power magnification
the cryoprecipitate appeared to be made up of a multitude of small spots closely apposed to one another.
At high power each spot was seen to consist of tubular structures identical to those encountered in the
endoneurium (Fig 6).
Several neuropathic manifestations may exist with
multiple myeloma [14, 241. The polyneuropathy in
most cases is symmetrical and of mixed motor and
sensory type. Cranial nerves may be involved [6].
The neuropathy is generally progressive, but remissions have been reported [28]. In 78% of reported
cases, CSF protein was elevated [ 141. No correlation
F i g 2. The endoneurial deposits exhibit a tubular c-onfiguration at higher magnification. They are distributed i n a
random manner and at times are i n direct contact with
Schwann cells. (Uranyl aretatellead citrate; ~ 2 0 , 0 0 0 . )
F i g 3 . Enlargrnent of the area shown in Figure 2 demonstrates
the tubular appearance of the deposit. (Uranyl acetatellead
citrate; ~45,000.)
Vallat et al: Cryoglobulinemic Neuropathy
F i g 4. Nerve capillary. Numerous inclujionj are seen within
the walls of the capillary (arrows). Some are outside the capillary i n the endoneurial space. { Uranyl acetatellead citrate;
x 4,900.)
F i g 5 . A capillary wall. A membrane-bound tubular inclusion
(arrow) is jeen within the cytoplasm of an endothelial cell (e).
Two other aggregates are present i n the space between the two
layers constituting the basement membrane of the capillary.
(Urunyl acetatellead citrate; x 16,000.)
182 Annals of Neurology Vol 8 No 2
August 1980
Pig 6. Tubular andjingerprint4ike aspect of the cryoprecipitate
iJolated from serum. (Uranyl acetatellead citrate; X40,OOO.)
exists between the severity of neuropathy and the
extent of myeloma, which may be solitary or multiple
[28]. The pathogenesis of myeloma neuropathy is
unclear and may differ from case to case. Cellular
infiltration, amyloidosis, and cryoglobulinemia have
all been proposed as possible mechanisms, as has endoneurial immunoglobulin deposition although the
presence of G component on myelin sheaths has not
been observed in myeloma neuropathy. In Waldenstrom’s disease, however, monoclonal IgM can
form deposits on myelin sheaths [22]. Rarely, patients with myeloma may develop chronic inflammatory polyradiculoneuropathy characteristic of the
Guillain-Bar& syndrome [l, 251.
Only a few ultrastructural studies of nerve biopsies
have been reported in myeloma neuropathy. Walsh
[JO] studied five biopsies and found reduced axon
number without evidence of demyelination or of
onion bulb formation. One of us with Vital [29] examined the biopsies of 5 patients. In that series,
nerve fiber abnormalities varied in intensity from
case to case, and 1 patient showed lesions of pure
segmental demyelination. Endoneurial changes were
not found, but none of these earlier patients had
cryoglo bulinemia.
In the patient reported here, it seems likely that
circulating cryoglobulins played an important role in
the pathogenesis of the peripheral neuropathy. Unusual complexes were observed in the nerve and
showed the same structure and tubular form as a
cryoprecipitate from the serum. This finding provides evidence that the tubular structures present
in nerve were in fact cryoglobulins. An attempt to
identify cryoglobulin deposits by immunofluorescent
analysis failed, possibly because the nerve tissue had
been embedded in paraffin before analysis or because
the cryoglobulin deposits were too small to be recognized by light microscopy.
Cryoglobulins are serum proteins that precipitate
in the cold and redissolve on warming. They may be
of two types [12]: (1) mixed, in which at least two
different immunoglobulins are present; this type has
been described in rheumatoid arthritis, systemic
lupus erythematosus, lymphomas, and infections,
although frequently no underlying cause is found;
and (2) single component, made up of a monoclonal
immunoglobulin; this type is characteristic of Waldenstrom’s macroglobulinemia and of myeloma and
was seen in the present case.
Peripheral neuropathies have been reported previously in patients with cryoglobulinemia [5, 7, 10,
12, 15, 18, 19, 23, 261. Logothetis et a1 [23] documented neuropathy in 9 out of 137 patients with
cryoglobulinemia, an incidence of 7 %. The clinical
Vallat et al: Cryoglobulinemic Neuropathy 183
picture has varied and appears to depend on the nature of the cryoglobulin. The same variability applies
to the histological lesions affecting the peripheral
nerves, which have been reported as either demyelinating [26] or axonal [12] in type. Dayan and
Lewis [15] and Cream et a1 [12] both noted lymphocytes and plasma cells in a perivascular distribution
extending through the perineurium into the nerve
fascicle in patients with cryoglobulinemia and
neuropathy, but in the present case no vasculitis was
In reviewing the literature, we have not found
an electron microscopic examination of peripheral
nerves in cryoglobulinemic neuropathy. The tubular
masses observed by us in the endoneurial space, in
the lumen, and in the walls of peripheral nerve capillaries have not been noted previously. Farivar et a1
[ 161 did isolate and characterize a serum cryoprotein
complex from a patient with chronic active hepatitis
and a severe peripheral neuropathy. Electron microscopic examination of the cryoprecipitate from
the serum in their case demonstrated aggregates of
tubular particles very much like the ones we observed in our patient. The ultrastructural features of
cryoglobulins vary. Sometimes they lack definite
structure; at other times fibrillary or, as observed by
us, curved, cylindrical, and annular profiles have been
seen [ 3 , 4, 11, 171. Feiner and Gallo [17] have suggested that the structural pattern of individual deposits may relate to specific cryoglobulin types. This
raises the possibility that structural configurations
may reflect specific physiochemical properties of
Possible mechanisms for the neuropathy in cryoglobulinemia have been much discussed. It seems
unlikely that a vasculitis, as suggested by Cream et a1
[12], can be incriminated as a cause of polyneuropathy in the patient reported here since vasculitis was
not observed in the nerve biopsy specimen on light
microscopy. A vascular ischemic process is more
probable, given the fact that we observed cryoglobulin deposits in the walls of pearly all capillaries
studied. On some occasions we saw the lumen of a
capillary occluded by a cryoglobulin mass; Feiner and
Gallo [17] noted similar thrombi in the glomerular
capillaries in 3 patients.
Our patient received low doses of vincristine for a
brief period. This drug can induce pathological
changes in the peripheral nervous system, especially
axonal degeneration [Z71; but abnormal deposits
have not been described in the endoneurial space in
vincristine neuropathy, and in the present case the
neuropathy was strikingly demyelinative.
The intravascular deposition of cryoproteins and
their high serum concentration in this patient suggest
that the cryoprotein may have interfered with local
184 Annals of Neurology Vol 8 No 2 August 1980
microcirculation, leading to ischemic injury to the
peripheral nerves. Large numbers of cryoglobulin
aggregates were identified in the endoneurial space.
Because we found no lymphocytes or plasmocytes
that could have secreted them in situ, we believe
these proteins originated from the general circulation. Possibly some of the abundant myelin lesions
reflected a direct pathological change affecting
Schwann cells induced by the cryoprecipitates, but
we were unable to demonstrate any clear relationship
between the abnormal material in the endoneurium
and nerve damage.
We are indebted to Dr Arthur K. Asbury and Dr Barry G. W.
Arnason for their helpful suggestions and to Dr Luchmaya for the
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Vallat et al: Cryoglobulinemic Neuropathy 185
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