Glue-Sniffing Neuropathy Rowena
Korobkin, MD; Arthur K. Asbury, MD; Austin J. Sumner, MD; Surl
Although industrial exposure to n-hexis known to cause neuropathy, it is less well recognized that inhalation of n\x=req-\ hexane present in the vapors of some ane
commercial contact cements is also neurotoxic to peripheral nerves. A young man with a long history of addictive glue-sniffing developed severe distal symmetrical polyneuropathy several months after switching to a cement containing n\x=req-\ hexane and gradually improved several months after switching to another cement containing no n-hexane. Fascicular biopsy of radial cutaneous nerve showed striking segmental distention of axons by neurofilamentous masses with secondary thinning of myelin sheath, paranodal myelin retraction, and widening of nodes of Ranvier. Nerve conduction velocities were correspondingly slow. We conclude that n-hexane used as a solvent in some contact cements may be neurotoxic when in-$ haled to excess and, further, that the neuropathy has characteristic electrophysiological and pathological features. (Arch Neurol 32:158-162, 1975)
Accepted for publication May 15, 1974. From the departments of neurology and pathology, School of Medicine, University of California at San Francisco, and Neurology Research Laboratory, San Francisco Veterans Administration Hospital. Read before the 49th annual meeting of the American Association of Neuropathologists, Freeport, Bahamas, June 16-18, 1973. Reprint requests to Department of Neurology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104 (Dr. Asbury).
L.
Nielsen,
MD
in¬ dustrial exposure to the solvent n-hexane is now both in this country1 and in Japan.2 It is less well known that glue-sniffing, the repeated inhalation of contact ce¬
from Polyneuropathy resulting widely recognized
ment vapors to
produce euphoria, can
also result in polyneuropathy if the cement contains n-hexane. In this study, we report the clinical features and distinctive neuropathologic and electrophysiologic aspects of a severe polyneuropathy occurring in a young man due to his practice of inhaling the vapors of a contact cement con¬ taining a high proportion of n-hex¬ ane. Because of the prevalence of glue-sniffing among young people,3 it is important for neurologists to be aware of this complication. REPORT OF A CASE man was hospitalized be¬ of progressive weakness of his ex¬ tremities and numbness of the fingers and toes. Symptoms began 2% months prior to admission, with aching pain in the calves and thighs after walking. Leg weakness gradually appeared, making walking diffi¬ cult and rendering him unable to arise from a sitting position without assistance. In the month preceding admission, he noticed mild weakness of the hands, as evi¬ denced by a tendency to drop objects and the inability to shuffle playing cards. He also noticed tingling of toes and, later, of fingertips. Blurring of vision was noted transiently, but had remitted before the patient sought medical aid. He had been impotent for the previous six months, but experienced no difficulty with hearing, bal¬ ance, or urinary bladder function.
A
29-year-old
cause
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The patient had been inhaling vapors of contact cement for about five years, in vol¬ umes up to 2 gallons per month. He would put % quart of fresh liquid cement into an empty 1-quart can and hold it, rim-to-face, inspiring through the mouth and expiring through the nose. This practice might be
continued for an hour or until he felt "high." A few months prior to the onset of symptoms he switched from a contact ce¬ ment containing no n-hexane to one that
did
(Table 1).
On examination, there was no physical evidence of liver disease. The hair was ab¬ sent on the lower legs. He exhibited nor¬ mal mental status except for an inappro¬ priate affect. The most striking findings was a wide-based slapping gait with in¬ ability to stand on either heels or toes. There was atrophy of the distal extremi¬ ties and weakness of most muscle groups in a symmetrical manner-distal weaker than proximal, legs weaker than arms. Deep tendon reflexes were all present and active except for absent ankle jerks. Pe¬ ripheral nerve trunks were normal to pal¬ pation. Sensory findings included severe position sense loss and mild vibratory sense loss in the lower extremities distally and hypesthesia to pin and touch in a glove stocking distribution over the feet to 5 cm above the malleoli and in the hands to mid-
palm. Although the patient was informed of a poor prognosis if he continued his habit of sniffing glue, he was unable to desist and
continued to sniff about 1 quart per week. However, he switched to a contact cement containing no n-hexane. Over the next three months, he became unable to walk without support, and sensory loss extended further proximally, especially in the lower extremities. By nine months after initial hospitalization, his clinical condition pia-
teaued, and he began
to
improve.
Table
Seventeen months after initial hospitali¬ zaron, he was walking with bilateral foot drop using crutches more for stabilization than strength and was able to use his hands well enough to play the guitar. At that time, hyperactive deep tendon re¬ flexes and a spastic catch in the lower ex¬ tremities became evident. Joint position sensation had improved, but vibratory sen¬ sation remained markedly diminished in the lower extremities. Results of hematological examination, serum electrolyte study, thyroid function studies, liver function tests, serum B-12 level study, glucose tolerance test, sero¬ logie test for syphillis, urinalysis, and chest x-ray film were all normal. The cerebrospi¬ nal fluid was acellular with a protein con¬ tent of 21 mg/100 ml.
SPECIAL INVESTIGATIONS Analysis of Contact Cement
1.—Analysis of Glue (280 gm) Solvent Lost by Evaporation,
% Total Product
Component
(by Weight)
Toluene n-hexane
Ethyl
30 min 24.6 19.6 2.5
44 27 10
acetate
gm
120 min
60 min 43.1 59.4
86.I 66.6 8.7
6.7
Table 2.—Motor Conduction Velocities Conduction Velocity,
Distal Latency,
meters/sec
Location
Patient 37 36 38 33.5 27.5 43
Right ulnar arm* Right ulnar forearm Right ulnar forearmt Right median forearm Right peroneal Right sciatic
msec
Normal Values
(SD 5.3) (SD 4.6) (SD 4.9) (SD 4.2) (SD 7.1) (SD = 3.3)
63.4 56.2 55.0 57.2 49.7 53.8
Patient
Normal Values
=
= =
= =
6.2 9.4 7.0 15.6 8.0
2.9 3.8 3.8 4.9 4.7
(SD (SD (SD (SD (SD
= = = = =
0.49) 0.53) 0.5) 0.9) 0.6)
*
Surface electrodes; abductor digiti minimi muscle. t Concentric needle electrode; first dorsal interosseus muscle.
The contents of were
a 1-quart (830 gm) can analyzed (Table 1). A 280-gm sample
of the cement
allowed to evaporate at temperature, and the residual vol¬ atile solvents were measured at intervals of 30, 60, and 120 minutes. From these val¬ ues, the maximum amount of solvents to which the patient was exposed after sniff¬ ing 1 quart of glue was calculated. We esti¬ mate that the n-hexane concentration ex¬ ceeded by manyfold the reported toxic industrial levels.1
Table
was
3.—Sensory
room
Clinical
Electrophysiology
Motor nerve conduction velocities were determined for several nerves in the right upper and lower extremities (Table 2). Velocities were notably reduced in all nerves examined, and distal motor laten¬ cies were greatly prolonged. Sensory nerve action potentials were of low amplitude or undetectable even using high gains and su¬
perimposed multiple traces (Table 3). Electromyographic examination with a
concentric needle electrode showed
changes of severe denervation in extensor digitorum brevis and abductor hallucis muscles. Profuse spontaneous fibrillation
potentials and positive sharp waves were evident, and on voluntary contraction, only two or three complex polyphasic units could be recorded discharging at high rates. In clinically less-involved intrinsic hand muscles, evidence of spontaneous de¬ nervation activity was not present, but during maximum voluntary effort, the pop¬ ulation of functioning motor units was es¬ timated to be reduced by 50%. The ampli¬ tude of the
compound
muscle action
potential recorded with surface electrodes from the right abductor digiti minimi
Nerve Action Potentials
Amplitude,
Latency
«v
Location
Patient
Right median Right ulnar Right sural
Normal Values 9-45
Absent Absent
8-24 15-62
muscle after supramaximal Stimulation of the ulnar nerve at the wrist was 4.0 mv. Six months later, motor conduction in the right ulnar nerve had fallen to 19 me¬ ters/sec, and distal motor latency was 7.6 msec. At 17 months, approximately 12 months after he stopped sniffing hexanecontaining glue and had shown appreciable clinical improvement, motor conduction velocities were still slowed, 30 meters/sec in the ulnar nerve and 29 meters/sec in the median nerve. A fascicular biopsy of the right radial cutaneous nerve was carried out. Portions of the nerve were processed for light and electron microscopy, and other portions were osmicated and teased apart under a dissecting microscope in liquid plastic em¬ bedding medium. In teased nerve fiber preparations, periodic discontinuous ta¬
pered axonal swellings were present within many myelinated axons (Fig 1, A and B). The myelin sheath overlying such formations appeared to be very thin or ab¬ sent. Occasionally, classical demyelinated segments beginning at a node of Ranvier were also observed (Fig 1, B). This axonal tected in light
abnormality easily de¬ microscopic preparations in was
to
Peak,
Patient 5.0
msec
Normal Values 2.5-4.0 2.2-3.4
both transverse and longitudinal sections, particularly in those stained by the Bodian silver protargol method (Fig 1, C and D). Swelling of axons with thinning of over¬ lying myelin sheath was even better ap¬ preciated in 2µ plastic sections (Fig 1, E and F). By electron microscopy, axonal swellings were composed of densely packed whorled masses of neurofilaments (Fig 2). Packets of other organelles includ¬ ing neurotubules, mitochondria, and smooth endoplasmic reticulum coursed in channels through the neurofilamentous masses (Fig 3). In addition to frequently observed thinning of myelin sheath over¬ lying axonal swellings, retraction of paranodal myelin sheath from nodes of Ranvier was
frequently present (Fig 4). Often, sev¬
eral supernumerary Schwann cells clothed the axon at widened nodal gaps (Fig 4). Active nerve fiber degeneration was ob¬ served infrequently, and most of the ex¬ pected nerve fiber complement was present.
COMMENT
A 29-year-old man sniffed as much 2 gallons of contact cement each month for five years. When he
as
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Fig 1.—A and B, Radial cutaneous nerve biopsy specimens. Portions of two myelinated fibers fixed in osmic acid and teased apart. Periodic swelling of fiber and thinning of myelin sheath is evident. Discontinuity of myelin without axonal distention at lower right represents ordinary segmental demyelination beginning at a node of Ranvier ( 85). C and D, Radial cutaneous nerve biopsy. Transverse (C) and longitudinal (D) sections stained for axons by switched to a cement containing nhexane, he developed during a fourmonth period progressive weakness and numbness of upper and lower ex¬ tremities until he became confined to a wheelchair and was barely able to hold the glue can to his face. Neuro¬ logical and electrophysiological exam¬ inations were consistent with poly¬ neuropathy, and this was confirmed by nerve biopsy. Since avoidance of exposure to n-hexane, clinical im¬ provement has occurred, after a lag period of several months. We con¬ clude that the neuropathy resulted from inhalation of n-hexane. In 1972, two descriptions of poly¬ neuropathy associated with gluesniffing were published. Gonzalez and
Downey reported
a
20-year-old
pa¬
tient with progressive distal motor and sensory neuropathy developing over a two-month period after 15 months of sniffing glue made of natu¬ ral crepe rubber and containing nhexane.4 Three months after dis¬ continuing the practice, the patient began to improve. Matsumura et al described severe polyneuropathy as"
Bodian protargol method. Some axons are severalfold enlarged (arrows) (C, 150; D, 180). E and F, Plastic section, 2µ, from radial cutaneous nerve biopsy specimen of patient (E) and from a normal human cutaneous nerve for comparison (F). Myelin sheaths around distended axons appear thinned (arrow) in pa¬ tient (E, X160; F, X175).
sociated with a one-year history of glue-sniffing in 18-year-old identical twin sisters.5 More recently, Shirabe et ale reported two cases of toxic poly¬ neuropathy due to glue-sniffing. Their patients had a similar clinical course including slight improvement three months after discontinuing the toxic inhalation. The degree of slowing of nerve conduction velocities observed in all four of these reported cases was similar to those reported in our pa¬ tient. Sural nerve biopsy was per¬ formed in all of the reported cases, but the described findings vary from those we found in our patient. Gonzal¬ ez and Downey4 found no histological abnormalities, and Matsumura et al5 reported slight reduction of large
myelinated fibers, segmental demye¬ lination, and axonal degeneration.
Shirabe et ale found loss of large fi¬ bers with relative sparing of small fi¬ bers and axonal degeneration. In all reports, n-hexane was considered to be the offending agent, although Shi¬ rabe and his group suggested that tolu¬ ene may have added to the problem. Many cases of polyneuropathy re-
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suiting
from
occupational
exposure to n-hexane
over-
known. In an epidemiological etudy of sandal workers in Japan, Yamamura de¬ scribed 90 cases of n-hexane poly¬ neuropathy from industrial expo¬ sure.2 A similar syndrome was reported in three cabinet finishers ex¬ posed to n-hexane in a furniture fac¬ tory in New York City by Herskowitz et al.1 There is a striking clinical sim¬ ilarity between the neuropathy ap¬ pearing in patients who sniff glue and those exposed industrially to n-hex¬ ane vapors. The clinical picture is that of a subacutely progressive dis¬ tal symmetrical weakness in all four extremities with hypoactive deep tendon reflexes, numbness, and oc¬ casionally dysesthesias or muscle tenderness, with rare cranial nerve involvement.1·2·4 Blurred vision was present in 14% of the cases reported from Japan and was also commented on by both our patient and the one re¬ ported by Gonzalez and Downey.4 In all patients exposed to n-hexane, in¬ cluding ours, there is a tendency to worsen for a time after exposure to nare
hexane has ceased, and the begin¬ nings of improvement are often de¬ layed for several months. Besides n-hexane, the cement used by our patient contained two other volatile substances, toluene and ethyl
known to have some effects. Toluene is re¬ psychotropic ported to produce feelings of drunk¬ enness, dizziness, and euphoria,1 while ethyl acetate has a narcotic effect.6 Toluene vapors have also been associ-
Fig 2.—Transverse section of portion of swollen axon in radial cutaneous nerve biopsy specimen. Myelin sheath is seen at left. Axoplasm is filled with dense array of neurofilaments in varying planes of ori¬ entation. A few scattered mitochondria, smooth vesicles, and neurotubules may also be identified ( 15,000).
Fig 3.—Enlarged axon in biopsied radial cutaneous nerve in longitudinal plane of section. Channel of normal organelles (ar¬ row), including smooth vesicles, neurotu¬ bules, and mitochondria, courses through the dense masses of neurofilaments. At upper right, axolemmal membrane is cov¬ ered by thin sheet of Schwann cell cyto¬ plasm, but no myelin sheath remains
acetate. Both
are
(x 10,000).
Fig 4.—Node of Ranvier of swollen axon in radial cutaneous nerve biopsy specimen in longitudinal plane of section. Paranodal myelin retraction has occurred, and super¬ numerary Schwann cell (S) has migrated into widened nodal gap. Arrow marks terminal myelin loops. Axon is distended by neurofilamentous masses (N) ( 8,500).
ated with clinical evidence of cerebellar degeneration.7·8 There is no re¬
ported toxicity
to
peripheral
nerves
associated with either toluene
ethyl
or
acetate.
An informal survey of retail stores Fran¬ cisco was undertaken. Cement is sold in large containers, up to 1 gallon, in "do-it-yourself" building supply stores and in smaller containers in hardware and hobby shops. Large cans may be readily purchased for a modest price ($7 to $8 per gallon). Of the five brands available, three con¬ tain n-hexane. Pathologically, the outstanding finding was segmental axonal en¬ largement due to masses of neurofila¬ ments. Axons were frequently swollen to two or three times expected diam¬ eter. Some degree of neurofilamen¬ tous accumulation is known to occur within proximal axons and also in neuronal perikarya, not only in such conditions as motor neuron disease9 and following intrathecal adminis¬ tration of vincristine,1" but also in ex¬ perimental intoxications with mitotic spindle inhibitors,11 aluminum salts,12 acrylamide,13 and B-B'-iminodiproprionitrile.14 None of these conditions has produced the degree of distal ax¬ onal enlargement seen in our patient. The only other human disorder that produces such striking axonal bulging from the accumulation of neurofila¬ mentous masses occurs in the recently described human condition, giant ax¬ onal neuropathy, which is thought to occur on a genetically determined basis.15 Other cases of giant axonal neuropathy have been recently dis¬ covered (R. Ouvrier, MD, written
selling contact cements in San
communication, April 30, 1974).1B The axonal abnormality seen in our
has not been previously de¬ scribed in n-hexane polyneuropathy. In a biopsy specimen from a severe case reported by Yamamura,2 "bal¬ looning and nodularity of axis cylin¬ der were rather prominent." Electron microscopy was not performed, and the observation was not further com¬ mented on. In the report by Herskowitz et al1 some increase in number of neurofilaments in intramuscular nerve twigs was observed, but with¬ out axonal distention. Recently, we
patient
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have had the nerve
biopsy
opportunity
to review
material from
a
second
of severe glue-sniffing poly¬ neuropathy, and an axonal abnormal¬ ity identical to that described in our patient was present. This observation strengthens our supposition that the neuropathologic changes are highly characteristic of n-hexane poly¬ neuropathy. case
An association between slow nerve conduction velocity and segmental demyelination is so well established that investigators commonly predict
the nature of the underlying patho¬ logical condition from nerve conduc¬ tion studies. Gilliatt17 has stated that motor conduction velocities that are reduced by 40% of normal mean val¬ ues, as in this case, are likely to indi¬ cate that the neuropathic process is demyelinative. In neuropathies pri¬ marily characterized by axonal de¬ generation, nerve conduction veloci¬ ties are little if any slowed. In our case, in which the primary process ap¬ pears to be axonal with accumulated neurofilamentous masses and axonal
ballooning, there are secondary ef¬ on the myelin coat with thin¬ of ning myelin sheath and marked widening of nodes created by retrac¬ tion of paranodal myelin. It is likely that the extreme nodal widening seen in this neuropathy is responsible for the slow impulse propagation; n-hex¬ ane appears to produce a primary axonal neuropathy with an unusual feature of severe slowing of periph¬ eral nerve conduction velocity. fects
The patient was referred for the Telfer, MD.
ert
study by
Rob¬
References 1. Herskowitz A, Ishii N, Schaumburg H: n\x=req-\ Hexane neuropathy. N Engl J Med 285:82-85, 1971. 2. Yamamura Y: n-Hexane polyneuropathy. Folia Psychiatr Neurol Jap 23:45-57, 1969. 3. Press E, Done A: Physiologic effects and community control measures for intoxication from the intentional inhalation of organic solvents: 1. Pediatrics 39:451-461, 611-622, 1967. 4. Gonzalez E, Downey J: Polyneuropathy in a glue sniffer. Arch Phys Med 53:333-337, 1972. 5. Matsumura M, Inoue N, Ohnishi A: Toxic polyneuropathy due to glue-sniffing. Clin Neurol 12:290-296, 1972. 6. Shirabe T, et al: Toxic polyneuropathy due to glue-sniffing. J Neurol Sci 21:101-113, 1974. 7. Baker A, Tichy F: Effects of organic solvents and industrial poisonings on central ner-
vous system. Proc A Res Nerv Men Dis 32:475\x=req-\ 505, 1953. 8. Grabski D: Toluene sniffing producing cere-
bellar
degeneration.
Am J
Psychiatr
118:461\x=req-\
462, 1961. 9. Carpenter S: Proximal axonal enlargement in motor neuron disease. Neurology 18:841-851,
1968. 10. Schochet S, Lampert P, Earle K: Neuronal changes induced by intrathecal vincristine sulfate. J Neuropathol Exp Neurol 27:645-658,1968. 11. Wisniewski H, Terry R, Hirano A: Neurofibrillary pathology. J Neuropathol Exp Neurol 29:163-176, 1970. 12. Terry R, Pena C: Experimental production of neurofibrillary degeneration: II. Electron microscopy, phosphatase histochemistry, and electron probe analysis. J Neuropathol Exp Neurol
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pennsylvania User on 06/12/2015
24:200-210, 1965.
13. Prineas J: The pathogenesis of dying-back neuropathies: II. An ultrastructural study of experimental acrylamide intoxication in the cat. J Neuropathol Exp Neurol 28:598-626, 1969. 14. Chou S, Hartmann H: Electron microscopy of focal neuroaxonal lesions produced by B-B1\x=req-\ iminodiproprionitrile (IDPN) in rats. Acta Neuropathol 4:590-603, 1965. 15. Asbury A, et al: Giant axonal neuropathy: A unique case with segmental neurofilamentous masses. Acta Neuropathol 20:237-247, 1972. 16. Carpenter S, et al: Giant axonal neuropathy: A second case. Neurology 23:429, 1973. 17. Gilliatt R: Nerve conduction in human and Proc R Soc Med 59:989-993, 1966.
experimental neuropathies.
Korobkin, MD; Arthur K. Asbury, MD; Austin J. Sumner, MD; Surl
Although industrial exposure to n-hexis known to cause neuropathy, it is less well recognized that inhalation of n\x=req-\ hexane present in the vapors of some ane
commercial contact cements is also neurotoxic to peripheral nerves. A young man with a long history of addictive glue-sniffing developed severe distal symmetrical polyneuropathy several months after switching to a cement containing n\x=req-\ hexane and gradually improved several months after switching to another cement containing no n-hexane. Fascicular biopsy of radial cutaneous nerve showed striking segmental distention of axons by neurofilamentous masses with secondary thinning of myelin sheath, paranodal myelin retraction, and widening of nodes of Ranvier. Nerve conduction velocities were correspondingly slow. We conclude that n-hexane used as a solvent in some contact cements may be neurotoxic when in-$ haled to excess and, further, that the neuropathy has characteristic electrophysiological and pathological features. (Arch Neurol 32:158-162, 1975)
Accepted for publication May 15, 1974. From the departments of neurology and pathology, School of Medicine, University of California at San Francisco, and Neurology Research Laboratory, San Francisco Veterans Administration Hospital. Read before the 49th annual meeting of the American Association of Neuropathologists, Freeport, Bahamas, June 16-18, 1973. Reprint requests to Department of Neurology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104 (Dr. Asbury).
L.
Nielsen,
MD
in¬ dustrial exposure to the solvent n-hexane is now both in this country1 and in Japan.2 It is less well known that glue-sniffing, the repeated inhalation of contact ce¬
from Polyneuropathy resulting widely recognized
ment vapors to
produce euphoria, can
also result in polyneuropathy if the cement contains n-hexane. In this study, we report the clinical features and distinctive neuropathologic and electrophysiologic aspects of a severe polyneuropathy occurring in a young man due to his practice of inhaling the vapors of a contact cement con¬ taining a high proportion of n-hex¬ ane. Because of the prevalence of glue-sniffing among young people,3 it is important for neurologists to be aware of this complication. REPORT OF A CASE man was hospitalized be¬ of progressive weakness of his ex¬ tremities and numbness of the fingers and toes. Symptoms began 2% months prior to admission, with aching pain in the calves and thighs after walking. Leg weakness gradually appeared, making walking diffi¬ cult and rendering him unable to arise from a sitting position without assistance. In the month preceding admission, he noticed mild weakness of the hands, as evi¬ denced by a tendency to drop objects and the inability to shuffle playing cards. He also noticed tingling of toes and, later, of fingertips. Blurring of vision was noted transiently, but had remitted before the patient sought medical aid. He had been impotent for the previous six months, but experienced no difficulty with hearing, bal¬ ance, or urinary bladder function.
A
29-year-old
cause
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The patient had been inhaling vapors of contact cement for about five years, in vol¬ umes up to 2 gallons per month. He would put % quart of fresh liquid cement into an empty 1-quart can and hold it, rim-to-face, inspiring through the mouth and expiring through the nose. This practice might be
continued for an hour or until he felt "high." A few months prior to the onset of symptoms he switched from a contact ce¬ ment containing no n-hexane to one that
did
(Table 1).
On examination, there was no physical evidence of liver disease. The hair was ab¬ sent on the lower legs. He exhibited nor¬ mal mental status except for an inappro¬ priate affect. The most striking findings was a wide-based slapping gait with in¬ ability to stand on either heels or toes. There was atrophy of the distal extremi¬ ties and weakness of most muscle groups in a symmetrical manner-distal weaker than proximal, legs weaker than arms. Deep tendon reflexes were all present and active except for absent ankle jerks. Pe¬ ripheral nerve trunks were normal to pal¬ pation. Sensory findings included severe position sense loss and mild vibratory sense loss in the lower extremities distally and hypesthesia to pin and touch in a glove stocking distribution over the feet to 5 cm above the malleoli and in the hands to mid-
palm. Although the patient was informed of a poor prognosis if he continued his habit of sniffing glue, he was unable to desist and
continued to sniff about 1 quart per week. However, he switched to a contact cement containing no n-hexane. Over the next three months, he became unable to walk without support, and sensory loss extended further proximally, especially in the lower extremities. By nine months after initial hospitalization, his clinical condition pia-
teaued, and he began
to
improve.
Table
Seventeen months after initial hospitali¬ zaron, he was walking with bilateral foot drop using crutches more for stabilization than strength and was able to use his hands well enough to play the guitar. At that time, hyperactive deep tendon re¬ flexes and a spastic catch in the lower ex¬ tremities became evident. Joint position sensation had improved, but vibratory sen¬ sation remained markedly diminished in the lower extremities. Results of hematological examination, serum electrolyte study, thyroid function studies, liver function tests, serum B-12 level study, glucose tolerance test, sero¬ logie test for syphillis, urinalysis, and chest x-ray film were all normal. The cerebrospi¬ nal fluid was acellular with a protein con¬ tent of 21 mg/100 ml.
SPECIAL INVESTIGATIONS Analysis of Contact Cement
1.—Analysis of Glue (280 gm) Solvent Lost by Evaporation,
% Total Product
Component
(by Weight)
Toluene n-hexane
Ethyl
30 min 24.6 19.6 2.5
44 27 10
acetate
gm
120 min
60 min 43.1 59.4
86.I 66.6 8.7
6.7
Table 2.—Motor Conduction Velocities Conduction Velocity,
Distal Latency,
meters/sec
Location
Patient 37 36 38 33.5 27.5 43
Right ulnar arm* Right ulnar forearm Right ulnar forearmt Right median forearm Right peroneal Right sciatic
msec
Normal Values
(SD 5.3) (SD 4.6) (SD 4.9) (SD 4.2) (SD 7.1) (SD = 3.3)
63.4 56.2 55.0 57.2 49.7 53.8
Patient
Normal Values
=
= =
= =
6.2 9.4 7.0 15.6 8.0
2.9 3.8 3.8 4.9 4.7
(SD (SD (SD (SD (SD
= = = = =
0.49) 0.53) 0.5) 0.9) 0.6)
*
Surface electrodes; abductor digiti minimi muscle. t Concentric needle electrode; first dorsal interosseus muscle.
The contents of were
a 1-quart (830 gm) can analyzed (Table 1). A 280-gm sample
of the cement
allowed to evaporate at temperature, and the residual vol¬ atile solvents were measured at intervals of 30, 60, and 120 minutes. From these val¬ ues, the maximum amount of solvents to which the patient was exposed after sniff¬ ing 1 quart of glue was calculated. We esti¬ mate that the n-hexane concentration ex¬ ceeded by manyfold the reported toxic industrial levels.1
Table
was
3.—Sensory
room
Clinical
Electrophysiology
Motor nerve conduction velocities were determined for several nerves in the right upper and lower extremities (Table 2). Velocities were notably reduced in all nerves examined, and distal motor laten¬ cies were greatly prolonged. Sensory nerve action potentials were of low amplitude or undetectable even using high gains and su¬
perimposed multiple traces (Table 3). Electromyographic examination with a
concentric needle electrode showed
changes of severe denervation in extensor digitorum brevis and abductor hallucis muscles. Profuse spontaneous fibrillation
potentials and positive sharp waves were evident, and on voluntary contraction, only two or three complex polyphasic units could be recorded discharging at high rates. In clinically less-involved intrinsic hand muscles, evidence of spontaneous de¬ nervation activity was not present, but during maximum voluntary effort, the pop¬ ulation of functioning motor units was es¬ timated to be reduced by 50%. The ampli¬ tude of the
compound
muscle action
potential recorded with surface electrodes from the right abductor digiti minimi
Nerve Action Potentials
Amplitude,
Latency
«v
Location
Patient
Right median Right ulnar Right sural
Normal Values 9-45
Absent Absent
8-24 15-62
muscle after supramaximal Stimulation of the ulnar nerve at the wrist was 4.0 mv. Six months later, motor conduction in the right ulnar nerve had fallen to 19 me¬ ters/sec, and distal motor latency was 7.6 msec. At 17 months, approximately 12 months after he stopped sniffing hexanecontaining glue and had shown appreciable clinical improvement, motor conduction velocities were still slowed, 30 meters/sec in the ulnar nerve and 29 meters/sec in the median nerve. A fascicular biopsy of the right radial cutaneous nerve was carried out. Portions of the nerve were processed for light and electron microscopy, and other portions were osmicated and teased apart under a dissecting microscope in liquid plastic em¬ bedding medium. In teased nerve fiber preparations, periodic discontinuous ta¬
pered axonal swellings were present within many myelinated axons (Fig 1, A and B). The myelin sheath overlying such formations appeared to be very thin or ab¬ sent. Occasionally, classical demyelinated segments beginning at a node of Ranvier were also observed (Fig 1, B). This axonal tected in light
abnormality easily de¬ microscopic preparations in was
to
Peak,
Patient 5.0
msec
Normal Values 2.5-4.0 2.2-3.4
both transverse and longitudinal sections, particularly in those stained by the Bodian silver protargol method (Fig 1, C and D). Swelling of axons with thinning of over¬ lying myelin sheath was even better ap¬ preciated in 2µ plastic sections (Fig 1, E and F). By electron microscopy, axonal swellings were composed of densely packed whorled masses of neurofilaments (Fig 2). Packets of other organelles includ¬ ing neurotubules, mitochondria, and smooth endoplasmic reticulum coursed in channels through the neurofilamentous masses (Fig 3). In addition to frequently observed thinning of myelin sheath over¬ lying axonal swellings, retraction of paranodal myelin sheath from nodes of Ranvier was
frequently present (Fig 4). Often, sev¬
eral supernumerary Schwann cells clothed the axon at widened nodal gaps (Fig 4). Active nerve fiber degeneration was ob¬ served infrequently, and most of the ex¬ pected nerve fiber complement was present.
COMMENT
A 29-year-old man sniffed as much 2 gallons of contact cement each month for five years. When he
as
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Fig 1.—A and B, Radial cutaneous nerve biopsy specimens. Portions of two myelinated fibers fixed in osmic acid and teased apart. Periodic swelling of fiber and thinning of myelin sheath is evident. Discontinuity of myelin without axonal distention at lower right represents ordinary segmental demyelination beginning at a node of Ranvier ( 85). C and D, Radial cutaneous nerve biopsy. Transverse (C) and longitudinal (D) sections stained for axons by switched to a cement containing nhexane, he developed during a fourmonth period progressive weakness and numbness of upper and lower ex¬ tremities until he became confined to a wheelchair and was barely able to hold the glue can to his face. Neuro¬ logical and electrophysiological exam¬ inations were consistent with poly¬ neuropathy, and this was confirmed by nerve biopsy. Since avoidance of exposure to n-hexane, clinical im¬ provement has occurred, after a lag period of several months. We con¬ clude that the neuropathy resulted from inhalation of n-hexane. In 1972, two descriptions of poly¬ neuropathy associated with gluesniffing were published. Gonzalez and
Downey reported
a
20-year-old
pa¬
tient with progressive distal motor and sensory neuropathy developing over a two-month period after 15 months of sniffing glue made of natu¬ ral crepe rubber and containing nhexane.4 Three months after dis¬ continuing the practice, the patient began to improve. Matsumura et al described severe polyneuropathy as"
Bodian protargol method. Some axons are severalfold enlarged (arrows) (C, 150; D, 180). E and F, Plastic section, 2µ, from radial cutaneous nerve biopsy specimen of patient (E) and from a normal human cutaneous nerve for comparison (F). Myelin sheaths around distended axons appear thinned (arrow) in pa¬ tient (E, X160; F, X175).
sociated with a one-year history of glue-sniffing in 18-year-old identical twin sisters.5 More recently, Shirabe et ale reported two cases of toxic poly¬ neuropathy due to glue-sniffing. Their patients had a similar clinical course including slight improvement three months after discontinuing the toxic inhalation. The degree of slowing of nerve conduction velocities observed in all four of these reported cases was similar to those reported in our pa¬ tient. Sural nerve biopsy was per¬ formed in all of the reported cases, but the described findings vary from those we found in our patient. Gonzal¬ ez and Downey4 found no histological abnormalities, and Matsumura et al5 reported slight reduction of large
myelinated fibers, segmental demye¬ lination, and axonal degeneration.
Shirabe et ale found loss of large fi¬ bers with relative sparing of small fi¬ bers and axonal degeneration. In all reports, n-hexane was considered to be the offending agent, although Shi¬ rabe and his group suggested that tolu¬ ene may have added to the problem. Many cases of polyneuropathy re-
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suiting
from
occupational
exposure to n-hexane
over-
known. In an epidemiological etudy of sandal workers in Japan, Yamamura de¬ scribed 90 cases of n-hexane poly¬ neuropathy from industrial expo¬ sure.2 A similar syndrome was reported in three cabinet finishers ex¬ posed to n-hexane in a furniture fac¬ tory in New York City by Herskowitz et al.1 There is a striking clinical sim¬ ilarity between the neuropathy ap¬ pearing in patients who sniff glue and those exposed industrially to n-hex¬ ane vapors. The clinical picture is that of a subacutely progressive dis¬ tal symmetrical weakness in all four extremities with hypoactive deep tendon reflexes, numbness, and oc¬ casionally dysesthesias or muscle tenderness, with rare cranial nerve involvement.1·2·4 Blurred vision was present in 14% of the cases reported from Japan and was also commented on by both our patient and the one re¬ ported by Gonzalez and Downey.4 In all patients exposed to n-hexane, in¬ cluding ours, there is a tendency to worsen for a time after exposure to nare
hexane has ceased, and the begin¬ nings of improvement are often de¬ layed for several months. Besides n-hexane, the cement used by our patient contained two other volatile substances, toluene and ethyl
known to have some effects. Toluene is re¬ psychotropic ported to produce feelings of drunk¬ enness, dizziness, and euphoria,1 while ethyl acetate has a narcotic effect.6 Toluene vapors have also been associ-
Fig 2.—Transverse section of portion of swollen axon in radial cutaneous nerve biopsy specimen. Myelin sheath is seen at left. Axoplasm is filled with dense array of neurofilaments in varying planes of ori¬ entation. A few scattered mitochondria, smooth vesicles, and neurotubules may also be identified ( 15,000).
Fig 3.—Enlarged axon in biopsied radial cutaneous nerve in longitudinal plane of section. Channel of normal organelles (ar¬ row), including smooth vesicles, neurotu¬ bules, and mitochondria, courses through the dense masses of neurofilaments. At upper right, axolemmal membrane is cov¬ ered by thin sheet of Schwann cell cyto¬ plasm, but no myelin sheath remains
acetate. Both
are
(x 10,000).
Fig 4.—Node of Ranvier of swollen axon in radial cutaneous nerve biopsy specimen in longitudinal plane of section. Paranodal myelin retraction has occurred, and super¬ numerary Schwann cell (S) has migrated into widened nodal gap. Arrow marks terminal myelin loops. Axon is distended by neurofilamentous masses (N) ( 8,500).
ated with clinical evidence of cerebellar degeneration.7·8 There is no re¬
ported toxicity
to
peripheral
nerves
associated with either toluene
ethyl
or
acetate.
An informal survey of retail stores Fran¬ cisco was undertaken. Cement is sold in large containers, up to 1 gallon, in "do-it-yourself" building supply stores and in smaller containers in hardware and hobby shops. Large cans may be readily purchased for a modest price ($7 to $8 per gallon). Of the five brands available, three con¬ tain n-hexane. Pathologically, the outstanding finding was segmental axonal en¬ largement due to masses of neurofila¬ ments. Axons were frequently swollen to two or three times expected diam¬ eter. Some degree of neurofilamen¬ tous accumulation is known to occur within proximal axons and also in neuronal perikarya, not only in such conditions as motor neuron disease9 and following intrathecal adminis¬ tration of vincristine,1" but also in ex¬ perimental intoxications with mitotic spindle inhibitors,11 aluminum salts,12 acrylamide,13 and B-B'-iminodiproprionitrile.14 None of these conditions has produced the degree of distal ax¬ onal enlargement seen in our patient. The only other human disorder that produces such striking axonal bulging from the accumulation of neurofila¬ mentous masses occurs in the recently described human condition, giant ax¬ onal neuropathy, which is thought to occur on a genetically determined basis.15 Other cases of giant axonal neuropathy have been recently dis¬ covered (R. Ouvrier, MD, written
selling contact cements in San
communication, April 30, 1974).1B The axonal abnormality seen in our
has not been previously de¬ scribed in n-hexane polyneuropathy. In a biopsy specimen from a severe case reported by Yamamura,2 "bal¬ looning and nodularity of axis cylin¬ der were rather prominent." Electron microscopy was not performed, and the observation was not further com¬ mented on. In the report by Herskowitz et al1 some increase in number of neurofilaments in intramuscular nerve twigs was observed, but with¬ out axonal distention. Recently, we
patient
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have had the nerve
biopsy
opportunity
to review
material from
a
second
of severe glue-sniffing poly¬ neuropathy, and an axonal abnormal¬ ity identical to that described in our patient was present. This observation strengthens our supposition that the neuropathologic changes are highly characteristic of n-hexane poly¬ neuropathy. case
An association between slow nerve conduction velocity and segmental demyelination is so well established that investigators commonly predict
the nature of the underlying patho¬ logical condition from nerve conduc¬ tion studies. Gilliatt17 has stated that motor conduction velocities that are reduced by 40% of normal mean val¬ ues, as in this case, are likely to indi¬ cate that the neuropathic process is demyelinative. In neuropathies pri¬ marily characterized by axonal de¬ generation, nerve conduction veloci¬ ties are little if any slowed. In our case, in which the primary process ap¬ pears to be axonal with accumulated neurofilamentous masses and axonal
ballooning, there are secondary ef¬ on the myelin coat with thin¬ of ning myelin sheath and marked widening of nodes created by retrac¬ tion of paranodal myelin. It is likely that the extreme nodal widening seen in this neuropathy is responsible for the slow impulse propagation; n-hex¬ ane appears to produce a primary axonal neuropathy with an unusual feature of severe slowing of periph¬ eral nerve conduction velocity. fects
The patient was referred for the Telfer, MD.
ert
study by
Rob¬
References 1. Herskowitz A, Ishii N, Schaumburg H: n\x=req-\ Hexane neuropathy. N Engl J Med 285:82-85, 1971. 2. Yamamura Y: n-Hexane polyneuropathy. Folia Psychiatr Neurol Jap 23:45-57, 1969. 3. Press E, Done A: Physiologic effects and community control measures for intoxication from the intentional inhalation of organic solvents: 1. Pediatrics 39:451-461, 611-622, 1967. 4. Gonzalez E, Downey J: Polyneuropathy in a glue sniffer. Arch Phys Med 53:333-337, 1972. 5. Matsumura M, Inoue N, Ohnishi A: Toxic polyneuropathy due to glue-sniffing. Clin Neurol 12:290-296, 1972. 6. Shirabe T, et al: Toxic polyneuropathy due to glue-sniffing. J Neurol Sci 21:101-113, 1974. 7. Baker A, Tichy F: Effects of organic solvents and industrial poisonings on central ner-
vous system. Proc A Res Nerv Men Dis 32:475\x=req-\ 505, 1953. 8. Grabski D: Toluene sniffing producing cere-
bellar
degeneration.
Am J
Psychiatr
118:461\x=req-\
462, 1961. 9. Carpenter S: Proximal axonal enlargement in motor neuron disease. Neurology 18:841-851,
1968. 10. Schochet S, Lampert P, Earle K: Neuronal changes induced by intrathecal vincristine sulfate. J Neuropathol Exp Neurol 27:645-658,1968. 11. Wisniewski H, Terry R, Hirano A: Neurofibrillary pathology. J Neuropathol Exp Neurol 29:163-176, 1970. 12. Terry R, Pena C: Experimental production of neurofibrillary degeneration: II. Electron microscopy, phosphatase histochemistry, and electron probe analysis. J Neuropathol Exp Neurol
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24:200-210, 1965.
13. Prineas J: The pathogenesis of dying-back neuropathies: II. An ultrastructural study of experimental acrylamide intoxication in the cat. J Neuropathol Exp Neurol 28:598-626, 1969. 14. Chou S, Hartmann H: Electron microscopy of focal neuroaxonal lesions produced by B-B1\x=req-\ iminodiproprionitrile (IDPN) in rats. Acta Neuropathol 4:590-603, 1965. 15. Asbury A, et al: Giant axonal neuropathy: A unique case with segmental neurofilamentous masses. Acta Neuropathol 20:237-247, 1972. 16. Carpenter S, et al: Giant axonal neuropathy: A second case. Neurology 23:429, 1973. 17. Gilliatt R: Nerve conduction in human and Proc R Soc Med 59:989-993, 1966.
experimental neuropathies.
