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Dysglobulinemic neuropathy Absence of immunoglobulin within myelin sheaths.

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Another catecholamine depletor, a-methyl-para-tyrosine,
can induce the acute dyskinetic syndrome in squirrel monkeys f4], which is compatible with the worsening of acute
dystonic reactions by this drug in one patient described by
Burke's group. The syndrome is also induced by the cholinergic agonist arecoline [4]. These and other findings led to
the proposal that this animal model is characterized by an
acute imbalance in dopamine and acetylcholine transmission
[4].The conclusions drawn by Burke and associates for acute
dystonic reactions are in complete agreement. The animal
model offers the potential for elucidating mechanisms involved in neuroleptic-induced extrapyramidal disorders.
CiBA-GEiGY Pbannacetlticds
556 Morris Awe
Summit, Nf 07901
Reply
Robert E. Burke, MD
We are grateful to Dr Liebman for bringing to our attention
his finding that tetrabenazine (TBZ) induces acute dyskinesia
in squirrel monkeys. The description of some of the involuntary movements in these animals, including writhing movements and persistent extension of the limbs, does suggest a
resemblance to human acute dystonia. These dyskinesias also
resemble acute dystonia in their time course and their clinical
pharmacology. Our report that TBZ induces acute dystonia
in humans provides further evidence of similar clinical
pharmacology. One major difference, however, between human dystonic reactions and squirrel monkey dyskinesias is
that the latter require chronic pretreatment with neuroleptics. In this respect they bear a closer resemblance to human
tardive dyskinesia. In addition, some of the dyskinesias include licking, biting, and tongue protrusions, which are features of tardive dyskinesia. Nevertheless, we agree with Dr
Liebman that most of the evidence, especially the clinical
pharmacology, suggests a relationship to acute dystonia.
Dr Liebman makes the very good point, based on experiments in monkeys, that the ability of TBZ to induce acute
dystonia may be due to its catecholamine-depleting properties rather than its dopamine receptor-blocking properties.
We postulated that the receptor-blocking properties were
responsible, based on the universal ability of dopamine receptor-blocking drugs to induce acute dystonia, and the inability of reserpine, another catecholamine depletor, to do
so. However, we recognize that other pharmacological differences between T B Z and reserpine, besides the receptorblocking properties of TBZ, may explain the ability of TBZ,
and not reserpine, to induce acute dystonia. For example,
TBZ depletes catecholamines more rapidly than does reserpine 151. Perhaps it is the rapidity of inhibition of central
dopaminergic transmission, rather than blockade, that is critical for the induction of acute dystonia.
Dr Liebman's observation that the cholinergic muscarinic
agonist arecoline is able to induce acute dyskinesias is fascinating in view of the hypothesis that human acute dystonic
reactions may be due to a sudden overactivity of central
cholinergic systems.
204 Annals of Neurology
Vol 19 No 2 February 1986
We agree that these animals offer potential for an improved understanding of neuroleptic-induced movement disorders in humans.
References
1. Burke RE, Reches A, Traub MM, et al: Tetrabenazine induces
acute dystonic reactions. Ann Neurol 17:200-202, 1985
2. Liebman JM, Neale R Neuroleptic-induced acute dyskinesias in
squirrel monkeys: correlation with propensity to cause extrapyramidal side effects. Psychopharmacology (Berlin) 68:25-29,
1980
3. Neale R, Gerhardt S, Fallon S, Liebman JM: Progressive changes
in the acute dyskinetic syndrome as a function of repeated elicitation in squirrel monkeys. Psychopharmacology (Berlin) 77:223228, 1982
4. Neale R, Gerhardt S , Liebman JM: Effects of dopamine agonists,
catecholamine depletors and cholinergic and GABA-ergic drugs
on acute dyskinesias in squirrel monkeys. Psychopharmacology
(Berlin) 82:20-26, 1984
5 . Pletscher A, Brossi A, Gey KF: Benzoquinolizine derivatives: a
new class of monoamine-decreasing drugs with psychotropic action. Int Rev Neurobiol 4:275-306, 1962
6. Weiss B, Santelli S, Lusink G: Movement disorders induced in
monkeys by chronic haloperidol treatment. Psychopharmacology
(Berlin) 53:289-293, 1977
Dysglobulinemic
Neuropathy : Absence
of Immunoglobulin
within Myelin Sheaths
Moses Rodriguez, MD,"
and Henry C. Powell, MB, BCh?
Peripheral neuropathy occurs in association with some
plasma cell dyscrasias, including monoclonal gammopathy of
undetermined significance [21. Using immunofluorescence
techniques, some investigators have found immunoglobulin
in the myelin sheaths of peripheral nerves from patients with
monoclonal gammopathy { 1, 4, 6, 71. Serum immunoglobulins from some patients with dysglobulinemic neuropathy
have also been found to bind to myelin sheaths in normal
nerve tissue 14, 61 and to a myelin-associated glycoprotein
separated from other myelin proteins 13, 4 , 61. Thus, the
uniform separation of the intraperiod lines of myelin sheath
that sometimes is seen in peripheral nerves of dysglobulinemic patients during electron microscopic study [4-6} has
been attributed on a theoretical basis to immunoglobulin
deposition.
We describe observations on nerves from two patients
who had a peripheral neuropathy associated with a serum
IgM kappa monoclonal protein of undetermined importance.
The clinical features of the patients have been reported as
Cases 4 and 5 in 151. The number of myelinated fibers was
decreased in sections of peripheral nerves from both patients; electron microscopy showed the myelin lamellae to be
uniformly separated (Figure, A). The initial goal of the study
was to demonstrate convincingly the deposition of Ig within
(A) Uniform separation of outer myelin lamellae (biphasic myelinopathy) in peripheral nerve of patient with chronicprogressive neuropathy and monoclonal gammopathy (Case 4 in {Sj).
Note absence of ultrastructural abnormalities within axon.
( X 20,000.) (B) Dark peroxidase-antiperoxidase reaction product (for IgM kappa) (Case 5 in {jj) is localizedprimarily in the
endoneurium but not on myelin sheaths of peripheral nerve. The
a r r w points t o a blood vessel that shows microangiopathy of the
vasa nervorum but does not stain for ISM. ( x 500.) (C) Same as
B but at a magnification of x 1,400. IgM is localized in the
subperineurium and endoneurium which intimately surrounds
myelin sheaths (arrow); no reaction product is directly present on
myelin. (D)Staining for the kappa light chain component. Note
dark reaction product localized exchsively to axons. ( x 1,200.)
myelin sheaths by using the peroxidase-antiperoxidase
(PAP) method on semithin Araldite sections. However, we
found IgM deposition within the subperineurium and endoneurium but no Ig in association with myelin sheaths.
Kappa light chains were deposited on axons.
Sections for staining were obtained from biopsied sural
nerves processed routinely for electron microscopy. The
specimens were fixed with 2.5 % phosphate-buffered glutaraldehyde, postfixed in osmium tetroxide, dehydrated in
graded alcohols, and embedded in Araldice resin. Semithin
sections were etched in sodium hydroxide and then stained
for IgM, IgG, kappa light chains, lambda light chains, and
human albumin using the PAP technique.
IgM was deposited exclusively in the subperineurium and
Annals of Neurology
Vol 19 No 2
February 1986 205
the endoneurial interstitium of the diseased peripheral
nerves (Figure, B). There was no reaction product on the
myelin sheaths (Figure, B and C) or within the epineurium or
the connective tissue of the perineurium (Figure, C). In some
fields, IgM was found in the immediate vicinity of the myelin
sheath but never directly on it (Figure, C). IgM was not
found along peripheral nerve blood vessels or endothelial
cells and did not show a perivascular distribution (Figure, B).
There was a notable absence of inflammatory cells, and no
cell carrying membrane-bound IgM was identified. Axons
did not exhibit the PAP reaction product. The same results
were obtained in similar experiments on frozen or paraffinembedded nerve tissue from these same patients.
IgG, albumin, and lambda light chains were also deposited
in the subperineurium, but the intensity of the PAP reaction
was much less than that with IgM. In contrast, kappa light
chains were present on axons but not on myelin sheaths
(Figure, D). There was some diffuse staining of the subperineurium and endoneurium, but the specificity was less
than that with the rabbit anti-IgM antibody.
In this immunocytochemical study there was no evidence
of Ig deposition in myelin even though electron microscopy
showed characteristic uniform separation of lamellae. In contrast, lg and albumin were readily demonstrated in the subperineurium and endoneurium, suggesting their passive diffusion into the interstitium after penetration of the bloodnerve barrier. Of additional note was the lack of inflammatory cellular infiltration and absence of Ig-producing cells
within the diseased peripheral nerves, suggesting that the Ig
was not synthesized in situ but may have diffused nonspecifically into the nerve. Similarly, complement has not
been reported within the nerves {l,4 , 7). These observations make it less likely that immune-mediated injury is responsible for the neuropathy. Our findings are in contrast to
those recently reported by Mendell and colleagues [ 4 ]in the
Annals, which emphasizes that these chronic neuropathies
represent a heterogeneous group of disorders.
The deposition of kappa light chains on axons was an unexpected finding. It is not clear, however, if the kappa light
chain plays a role in the pathogenesis of the neuropathy.
'Department of Neurology and the ExperimentalNeuropatbology
Laboratory
Mayo Clinic and Mayo Foundation
Rocbester, M N 55905
?Department of Pathology
University of California
San Diego, C A 92093
M. R. is the recipient of Teacher Investigator Award NS 00847
from the National Institutes of Health and is a Rapaport Scholar of
the Mayo Clinic and Mayo Foundation.
The authors gratefully acknowledge the expert technical assistance
of Mabel L. Pierce. We also thank Dr Vanda A. Lennon for her
review of the manuscript.
Refrences
1. Dalakas MC, Engel WK: Polyneuropathy with monoclonal gammopathy: studies of 11 patients. Ann Neurol 10:45-52, 1781
2. Kelly JJ Jr, Kyle RA, O'Brien PC, Dyck PJ: Prevalence of mono-
206 Annals of Neurology Vol 19 N o 2 February 1986
3.
4.
5.
6.
7.
clonal protein in peripheral neuropathy. Neurology (NY)
31:1480-1483, 1981
Latov N , Braun PE, Gross RB, et al: Plasma cell dyscrasia and
peripheral neuropathy: identification of the myelin antigens that
react with human paraproteins. Proc Natl Acad Sci USA
78:7139-7142, 1781
Mendell JR, Sahenk 2, Whitaker JN, et al: Polyneuropathy and
IgM monoclonal gammopathy: studies on the pathogenetic role
of anti-myelin-associated glycoprotein antibody. Ann Neurol
17:243-254, 1785
Powell HC, Rodriguez M, Hughes RAC: Microangiopathy of
vasa nervorum in dysglobulinemic neuropathy. Ann Neurol
15:386-374, 1784
Stefansson K, Marton L, Antel JP, et al: Neuropathy accompanying IgMh monoclonal gammopathy. Acta Neuropathol 59:255261, 1983
Swash M, Perrin J, Schwartz MS: Significance of immunoglobulin
deposition in peripheral nerve in neuropathies associated with
paraproteinaemia. J Neurol Neurosurg Psychiatry 42:177- 183,
1779
Intravascdar Contrast
Media and Neuromuscular
Junction Disorders
P. Van den Bergh, MD, J. J. Kelly, Jr, MD,
B. Carter, MD," and T. L. Munsat, M D
W e report a patient with the Eaton-Lambert myasthenic syndrome (ELMS), who developed a myasthenic crisis during
intravenous infusion of meglumine diatrizoate 30% (RenoM-DIP; Squibb).
The patient, a 48-year-old white man, was first examined
because of a presumptive diagnosis of myasthenia gravis
(MG). He experienced limb weakness, dysphagia, dysarthria,
mild dyspnea, mild bilateral ptosis, blurring of vision, and
paresthesias in both hands and feet. Serum acetylcholine receptor antibodies were absent. After an initially good response to pyridostigmine bromide and prednisone, the patient's condition deteriorated over the next few months.
O n examination, left-sided ptosis with lid fatigability, mild
bilateral abducens paresis, slight dysarthria, and moderate
weakness of the neck and all four extremities were found.
Handgrip facilitated markedly (Lambert's sign). Deep tendon
reflexes were 1 +, except for absent ankle reflexes. Vital
capacity was 2.7 liters. Electromyography (EMG) showed
short-duration, low-amplitude motor unit action potentials
which were markedly unstable. Single-fiber EMG revealed
increased jitter, especially at lower rates of MUAP activation.
All motor nerve conduction velocities obtained were normal, but evoked compound muscle action potential (CMAP)
amplitudes were low with marked post-exercise facilitation
of CMAPs. The diagnosis of ELMS was made. Treatment
with guanidine, low-dose prednisone, and plasmapheresis resulted in moderate but definite improvement. Thyroid function tests, creatine kinase levels, chest x-ray studies, bronchoscopy, bronchial aspirate and sputum cytology, bone
marrow aspirate and biopsy, and mediastinal and abdominal
computerized tomography (CT) were normal.
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