The Bruns-Garland
Syndrome (Diabetic Amyotrophy)
Revisited 100 Years Later Richard J.
Barohn, MD; Zarife Sahenk, MD; John R. Warmolts, MD; Jerry R. Mendell, MD
\s=b\ A group of 17 patients had proximal diabetic neuropathy characterized by abrupt onset of asymmetric pain and weakness. Fourteen patients had unilateral onset that later involved the other extremity in 3 days to 8 months. All patients reported stepwise or steady progression during 2 to 18 months that was documented during serial examinations. In 16 patients, both proximal and distal muscles were involved. Sural nerve biopsy specimens demonstrated multifocal variability in nerve fiber density manifesting as nonrandom fiber loss between and within fascicles compared with age-matched controls. These findings demonstrate that patients may have a rapidly evolving course of proximal diabetic neuropathy followed by continued progression for many months and emphasize the overlap between proximal diabetic neuropathies of presumed different types. Our cases and others cast doubt on notions supporting two distinct types of proximal diabetic neuropathies represented by the rapid evolution of asymmetric weakness on an ischemic basis, in contrast to a more slowly progressive condition of metabolic pathogenesis. (Arch Neurol. 1991 ;48:1130-1135)
"1 he syndrome originally described by Bruns1 and later by Garland and Taverner,2"0 who coined the term diabet¬ ic amyotrophy, continues to be a topic for debate and discussion 100 years afAccepted for publication April 15,1991.
From the Division of Neuromuscular Disease, Norman Allen Department of Neurology, Ohio State University Hospital, Columbus. Dr Barohn is now with the Division of Neurology, Department of Medicine, University of Texas Health Science Center at San Antonio. Reprint requests to Norman Allen Department of Neurology, Ohio State University Hospital, 410 W 10th Ave, Columbus, OH 43210-1228 (Dr
Mendell).
ter its
original description. These au¬ thors described a disorder character¬ ized by severe pain in the hip and thigh followed by asymmetric weakness and wasting affecting the leg muscles. Skep¬ tics originally questioned the existence of this syndrome, as reflected by Gar¬ land's0 statement before the British Royal Society of Medicine in 1960: "The reaction of others to my first paper is varied; many thought this was merely a product of my Leeds' imagination but most neurologists soon found one or more examples." A series of subsequent reports did, in fact, confirm the occur¬ rence of this entity.""14 The name diabet¬ ic amyotrophy, referring to the weak¬ ness and wasting, has proved clumsy, however, and a variety of descriptive terms have been used to refer to this disorder: diabetic proximal amy¬ otrophy,1'1 proximal diabetic neuropa¬ thy,lh"18 diabetic lumbosacral plexopathy,19-20 ischemie mononeuropathy multiplex,2122 femoral-sciatic neuropa¬ thy,23 and femoral neuropathy.24'20 An important controversy in this dis¬ ease relates to the issue of how many types of so-called diabetic amyotrophy exist. Presumably there are two dis¬ tinct disorders with different pathogen¬ ic mechanisms. Raffet al21,22 described a patient with abrupt onset of proximal and distal weakness in one leg. Evi¬ dence favoring an ischemie pathogene¬ sis was provided by an autopsy study showing infarcts of the proximal major nerve trunks of the leg and lumbosacral plexus sparing spinal roots and spinal cord. In contrast, Chokroverty et al15'26"28 emphasized an insidious, usually bilat¬ eral disorder, predominantly affecting proximal muscles due to a selective met-
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abolie insult affecting the distal branches ofthe proximal motor nerves, "a proximal intramuscular crural neu¬
ropathy."26
We studied a group of patients fulfill¬ the descriptive criteria of Bruns1 and Garland and Taverner2"0 who dem¬ onstrated an abrupt onset of pain and asymmetric weakness affecting the proximal and distal leg muscles and also exhibited subacute progression for up to 18 months. These findings suggest that presumed distinct types of proxi¬ mal diabetic neuropathies do not repre¬ sent separate, unrelated entities with different pathogenic mechanisms.
ing
PATIENTS AND METHODS
Clinical, laboratory, and biopsy results reviewed from 17 consecutive patients
were
(14 women and three men) who were exam¬ ined between January 1984 and July 1988 at the Neuromuscular Service at Ohio State University, Columbus. The diagnosis of proximal diabetic neuropathy, also referred to as diabetic lumbosacral radiculoplexopathy, was made on the basis ofthe following criteria: (1) onset of diabetes mellitus2" either before or at the onset of neurologic symp¬ toms; (2) abrupt onset of hip, back, or leg pain, either unilateral or bilateral; (3) weak¬ ness ofthe lower extremities involving proxi¬ mal muscles or proximal and distal muscles, unilaterally or bilaterally (patients with weakness confined to a peripheral-nerve dis¬ tribution were excluded); (4) results of elec¬ trophysiologic studies excluding myopathy; and (5) lumbosacral magnetic resonance im¬
computed tomograms, or myelograms excluding neoplastic disease, multiple com¬ pressive radiculopathy, and spinal stenosis. On the initial and all subsequent patient visits, manual muscle strength testing was performed on 32 muscle groups; results were graded with a modified Medical Research Council scale expanded to a 10-point system ages,
Arms
10 »
9H
Arms
10 9 8 8 co 7 ö 6
HF HA HE KE KF AD AE Al AP
1?
Legs
*
m
I
HF HA HE KE KF AD AE Al AP
o
2
< 1
0
2 4 6 8 1012141618202224
Months Arms
10 9
8
co
>
8 7 6
U o
S ;
"» CJ) Q ¿
2· < 1 0
Arms
10 9 8
Legs
: 5
4
3 S 2·
AP 10
0
Months
R
L
HF 7 HA 3 HE 2 KE10 KF 7 AD 7 AE 7 Al 7 AP 7
H
4 6 8 1012141618202224
3 3 3 3 1 0 0 0 7
2 4 6 8 1012141618202224 Months
f
CO
R_
2 4 6 8 1012141618202224 Months
matched controls. All nerve fascicles from each biopsy specimen were photographed and printed at a final magnification of 430. Each fascicle was divided into four quadrants by horizontal and vertical lines (ie, longest and shortest dimensions of an ellipsoid), and all myelinated fibers with diameters greater than 3.5 µ were counted in each quadrant. The cross-sectional area for each quadrant, as well as for the entire fascicle, was mea¬ sured by means of a visual image analyzing system (VIAS, Ted Pella Ine, Tustin, Calif). The myelinated fiber density, expressed as the number per 10,f µ 2 area for each quad¬ rant and for the whole fascicle, was plotted separately for each fascicle from patients and controls. The variability of myelinated fiber density was estimated by calculating the co¬ efficient of variation among quadrants within fascicles and between fascicles as modified from the method described by Dyck et al.34 The Wilcoxon Rank-Sum Test was done to determine the significance of nonrandom fi¬ ber distribution and loss compared with con¬ trols. In the course of this study, a total nerve area of 6.799 mm2 from patients and 2.690 mm" from controls was analyzed.
R
I8
.Arms HFHA3 _Legs HE3
5 5 2 4. 3 S, i? 2. S 1 0
KE7 KF4 AD1 AE 1 Al 1 AP2 I I I I I f f I 10 14 18 22 26 30 34 56 Months
210
8
co en
7 6
2
6
RESULTS Patient Population
The patient population included 17 patients (three men and 14 women) ranging in age from 47 to 77 years (mean± SD, 66.4 ±7.62 years). A diag¬
14 18 22 26 30 34 Months
_
Fig 1.—Course of muscle strength in six patients showing progressive leg weakness. Broken lines represent the period before the initial evaluation. Solid lines represent the course during our serial examinations. The average muscle score, shown in the table adjacent to each graph, is based on a modified Medical Research Council scale expanded to a 10-point scale (see text). The scores for leg strength are those at the nadir of the illness. R indicates right; L, left; HF, hip flexion; HA, hip abduction; HE, hip extension; KE, knee extension; KF, knee flexion; AD, ankle dorsiflexion; AE, ankle eversión; Al, ankle inversion; and AP, ankle plantar flexion.
nosis of diabetes mellitus was estab¬ lished before onset in 12 patients (71%). Three were taking insulin, six were tak¬ ing oral hypoglycémie agents, and in three the condition was controlled by diet. In five patients, a diagnosis of dia¬ betes mellitus was established coinci¬ dent with the onset of neurologic
symptoms.
Clinical Features
and summated to give an average muscle score'1" as follows: 0 was scored as 0; 1,1; 2, 2; 3-, 3; 3, 4; 3 + , 5; 4-, 4, and4 +, 7; 5-, 9; and 5, 10. Muscles tested included neck flex¬ ors, neck extensors, shoulder abductors, el¬ bow extensors, elbow flexors, wrist flexors, wrist extensors, thumb abductors, hip flex¬ ors, hip extensors, hip abductors, knee ex¬ tensors, knee flexors, ankle dorsiflexors, an¬ kle evertors, ankle invertors, and ankle plantar flexors. Eleven ofthe 17 patients had detailed follow-up at 1- or 2-month intervals. Six patients were seen initially but did not return.
Electrophysiologic Studies
Electrophysiologic studies were per¬ according to methods previously de¬
formed
scribed." Standard techniques were used for motor and sensory conduction studies by means of surface electrode recording. Electromyograms were performed on proximal and distal upper- and lower-extremity mus¬ cles. Fibrillation potentials were graded on a scale32 of 0 to 4 +, where 0 indicates no fibril¬ lations; 1 +, single persistent runs in at least two areas; 2 +, moderate numbers in three or
areas; 3 +, many fibrillations in all ar¬ eas; and 4 +, fibrillations completely filling more
the baseline.
Nerve Biopsy
Sural nerve biopsy specimens were ob¬ tained from 10 patients who were under local anesthesia, as previously described." The specimens consisted of a 4-cm segment of nerve fixed by immersion in 3% glutaraldehyde in 0.1-mol/L phosphate buffer for 30 minutes at room temperature at the in situ length. The nerve was then cut into small blocks and returned to the same fixative for an additional 2 hours, followed by postfixa¬ tion in 1% osmium tetroxide in 0.1-mol/L phosphate buffer for 2 hours. After dehydra¬ tion in graded concentrations of alcohol and propylene oxide, tissue blocks were embed¬ ded in low-viscosity embedding medium. Cross sections of nerve, 1 µ thick, were stained with toluidine blue. Morphometric analysis included assess¬ ment of myelinated nerve fiber density and the spatial pattern of nerve fiber loss be¬ tween and within nerve fascicles from biopsy specimens of 10 patients and four age-
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Pain at the onset was reported as uni¬ lateral in 14 patients and bilateral in three. At the time of initial evaluations, pain had progressed to become bilateral in all patients. In patients with unilater¬ al onset, latency to involvement of the second leg (by history) ranged from 3 days to 8 months. The pain, most severe in the back and hip, was characterized as aching, burning, and knifelike. Only seven of 17 patients complained of numbness or paresthesias in the lower extremities. By neurologic examina¬ tion, however, more patients had de¬ monstrable sensory loss in a stocking distribution. Vibratory loss was most common below the ankles and occurred in 14 patients (82%). Nine patients (53%) had decreased pin, touch, and temperature sense below the ankles. No sensory loss in a radicular or periph¬ eral-nerve distribution was observed. Muscle weakness was confined to the lower extremities. From onset until na¬ dir, all patients reported steady or step-
wise progression of weakness for 2 to 18 months (mean ± SD, 8.6 ±3.3 months). Four patients had progression for more than 1 year. In all patients, weakness was bilateral. At the initial evaluation, 16 of 17 patients exhibited asymmetric leg weakness that involved both proxi¬ mal and distal muscles. In six cases, the weakness at the hip and knee was great¬ er than that at the ankle, but in the remainder, proximal and distal muscles were equally affected. Follow-up evalu¬ ations were performed in 11 patients after 6 to 44 months (mean ± SD, 21.5 ± 13.1 months). In six patients, un¬ equivocal loss of strength occurred after the initial evaluation, as illustrated by plots of muscle strength (Fig 1). Only one of 11 patients who were followed up demonstrated a return to normal strength. Seven of 11 patients had com¬ plete resolution of pain. Tendon reflexes were absent in the lower extremities in 16 of 17 patients. In the arms, tendon reflexes were absent in five and diminished in one. Five patients reported losing sub¬ stantial amounts of weight, ranging from 13.5 to 36 kg at the time of initial evaluation.
Laboratory Studies
Fasting blood glucose levels spanned a wide range at the time of presentation (5.2 to 15.5 mmol/L), with levels above normal (>6.9 mmol/L) in 14 patients. The three patients in whom the fasting blood glucose levels were normal (5.2, 5.2, and 5.6 mmol/L) were known dia¬ betics; one was taking insulin, one was taking an oral hypoglycémie agent, and
by diet therapy. The Westergren erythrocyte sedimentation one was
treated
(normal, 2
38.2 ± 1.9t
5.6 ± 0.5
Fig 2. —Cross sections of sural nerve fascicles, 1 µ thick, from patient 4 illustrating adjacent fascicles. Nonrandom fiber loss more apparent and more severe in the left than in the right (toluidine blue, original magnification 312).
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Normal Value
SD) 4.0*
±
>5
is
9
C2
C1
C4
C3
8.
fII
6-
S5 < ja
5-
3
4.
^
3.
o
1 i'
-
'
2-
8
10
9
Patient 3.—The graph shows the myelinated fiber density (number/1 OV™2) for each quadrant (small closed circles) and for the whole fascicle in diabetic patients (patient 1 through patient 10; open circles show the fiber density for the entire fascicle) and in controls (1 through C4; large closed circles show the fiber density for each fascicle) shown at the top.
Fig
Spatial Pattern of Fiber Loss.— Morphometric studies demonstrated a significant reduction in the myelinated fiber density in all patients (3251.9 ± 1729.30/mm2; 10) com¬ with control pared subjects (7093 ± 609.07/mm2; 4). The mean fi¬ ber density for controls was comparable with previously published values.'*4 In addition, there was an increased vari¬ ability in the distribution of myelinated nerve fibers per square millimeter (Fig 3). Figure 3 shows the number of my¬ =
=
elinated fibers per 3 µ 2 for each quadrant and for the whole fascicle for patients and controls. A marked vari¬ ability in fiber density between and within fascicles was evident in all pa¬ tients, consistent with nonrandom nerve fiber loss. Patients 1, 3, 4, and 7 exhibited a greater variability than did others. The coefficient of variation was significantly different both between and within fascicles in diabetics compared with controls (P=.002 between fasci¬ cles; P= .004 within fascicles; Table 2). REPORT OF PATIENTS
The following cases reflect the clinical and pathologic spectrum of diabetic lumbosacral plexopathy observed in this group (patient numbers correspond to those in Fig 3 and Table 2).
PATIENT 4. —A 67-year-old man without a history of diabetes mellitus developed sud¬ den pain in the right thigh. Four weeks later, he experienced identical pain on the left side, accompanied by bilateral weakness. His fam¬ ily physician documented an elevated fastingblood glucose level of 13.32 mmol/L and placed him on dietary control. The Westergren erythrocyte sedimentation rate was 10 mm/h. Symptoms were accompanied by a 13.5-kg weight loss. After 4 months of pro¬ gression, resulting in difficulty in ambulation and frequent falls, the patient was referred
Table 2.—Spatial Pattern of Fiber Loss Coefficient of Within
Fasciclest Patient 1 2
3 4 5 6
to the Neuromuscular Center at Ohio State
7
University Hospitals. On neurologic examination, there was asymmetric leg weakness involving proximal and distal muscles (Fig 1, top left). A patchy loss of touch and pin sensation occurred over the thighs and lower part of the legs and did not correspond to a peripheral-nerve or ra¬
dicular distribution. Vibration sense was re¬ duced in the left foot only. Hyporeflexia was present in the arms, and tendon reflexes were absent in the legs. Peroneal motor conduction velocity was 37.8 m/s, with a distal latency of 6.1 millisec¬ onds, and amplitude was mildly reduced (1.5 mV). The sensory action potential ofthe sural nerve was unobtainable. Electromyog¬ raphy disclosed widespread fibrillation po¬ tentials (3 + to 4 + ) in the right and left proxi¬ mal and distal lower-extremity muscles. Initially only the distal part of the left leg showed denervation potentials, but during follow-up, 2 to 3 + fibrillation potentials were observed in the right anterior tibialis and
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8 9
10
0.241 0.117 0.442 0.208
0.136
Variation* Between Fascicles 0.366 0.112 0.498
0.739
0.156 0.356 0.142 0.126 0.203
0.232 0.173 0.330 0.167 0.080 0.202
0.087 0.129 0.075 0.100
0.075 0.049 0.072 0.085
Control 1
2
3 4 *
variability of myelinated fiber density was es¬ by calculating the coefficient of variation among quadrants within fascicles and between fasci¬
The timated
cles.
tAveraged values for fascicles.
gastrocnemius muscles, which had been nor¬ mal on the initial electromyographic examination. A left sural nerve biopsy specimen (Fig 2) showed nonrandom, multifocal loss of my¬ elinated nerve fibers within and between fas¬ cicles (also see data for patient 4 [Fig 3, Table 2]). Fibers in various stages of axonal degen-
eration were present. Occasional thinly my¬ elinated fibers with excessive Schwann cell processes were seen. No clusters of regener¬
ating axons were present. Clinical follow-up documented worsening for 5 additional months (total progression over 9 months), with subsequent gradual re¬ turn of strength (Fig 1, top left). Twentyfour months after onset, the patient still had considerable residual weakness. The
severe
pain had resolved, and he had persistent dull aching at night. Comment.—A
previously undiag¬
nosed diabetic developed unilateral and then bilateral leg pain and weakness in an asymmetric distribution involving proximal and distal muscles. Follow-up evaluations documented progression for 5 months. The sural nerve biopsy specimen showed a multifocal pattern of nerve fiber loss between and within fascicles. PATIENT 6.—A
58-year-old man with his¬
tory of diet-controlled diabetes mellitus de¬
veloped sudden severe back pain radiating into both legs. He noticed bilateral progres¬ sive leg weakness within days. He was re¬ ferred to the Neuromuscular Center at Ohio State University 2 months after the onset of symptoms. Neurologic examination dem¬ onstrated mildly asymmetric leg weakness involving proximal and distal muscles (Fig 1, center left). A stocking-pattern loss of pin, touch, and vibration sense was present. Ten¬ don reflexes were normal in the arms and absent in the legs. Fasting blood glucose level was mildly ele¬ vated at 8.22 mmol/L, with a normal glycosy¬ lated hemoglobin fraction of 7.0% (normal, 5.5% to 8.4%). Westergren erythrocyte sedi¬ mentation rate was 9 mm/h. The peroneal conduction velocity was mildly slow at 40 m/s, but the amplitude ofthe compound mo¬ tor action potential was significantly reduced at 300 mV. The sural nerve conduction veloc¬ ity was 38 m/s, with 5-µ" amplitude. Median and ulnar motor and sensory conduction ve¬ locities were normal. An electromyogram re¬ vealed 2 + to 3 + fibrillation potentials in the proximal and distal muscles bilaterally. A sural nerve biopsy specimen (obtained 5 months after the onset of symptoms) demonstated a nonrandom pattern of nerve fiber loss between and within fascicles, with a sig¬ nificant reduction in nerve fiber density (Fig 3, Table 2). Two months after the initial referral dem¬ onstrated more severe weakness (Fig 1, cen¬ ter left). Continued follow-up demonstrated a stepwise course with documented periods of improvement and deterioration in strength. Eleven months after the onset of symptoms, the patient's condition began to
improve steadily.
Comment.—Bilateral, asymmetric, painful, proximal and distal leg weak¬ ness developed abruptly in a known dia¬ betic. He continued to have stepwise deterioration for 11 months before sus¬ tained improvement occurred. A sural nerve biopsy specimen obtained after 5
months of progression showed a random pattern of nerve fiber loss.
non-
PATIENT 7.—A 65-year-old diabetic wom¬ treated with an oral hypoglycémie agent developed sudden severe pain in the lower part of her back that radiated to the left leg, which became weak 2 days later. After 1 month, identical pain and weakness occurred in the right leg. Symptoms persisted for 5 months, at which time an L-5 radiculopathy was diagnosed by myelography. A lumbar laminectomy was performed but did not re¬ lieve the pain or weakness. The leg symp¬ toms were accompanied by a 9-kg weight loss. Ten months after the onset, she was referred to the Neuromuscular Center at Ohio State University. On neurologic examination, asymmetric proximal and distal leg weakness was pre¬ sent with atrophy ofthe quadriceps and ham¬ string muscles, worse on the left (Fig 1, top right). A stocking-pattern loss of pin, touch, and vibration sense was present. Tendon re¬ flexes were absent at the knees and ankles. Upper extremities showed no changes in strength, reflexes, or results of sensory an
testing.
At the time of the initial evaluation, the fasting blood glucose level was 14.99 mmol/L, with an elevated glycosylated he¬ moglobin fraction of 10.3%. The Westergren erythrocyte sedimentation rate was mildly elevated at 37 mm/h. Peroneal compound mo¬ tor action potential and sural sensory poten¬
tials were unobtainable. Median motor nerve conduction was 44 m/s (normal, >48 m/s), with prolonged distal latency of 7.1 millisec¬ onds (normal, 4 mV). In the legs, denervation potentials were abundant (3+ to 4 + ) in proximal (vastus lateralis and gluteus médius) and distal (gas¬ trocnemius and anterior tibial) muscles
bilaterally.
A sural nerve biopsy specimen (obtained after 10 months of progressive symptoms) revealed a marked loss of large myelinated fibers that was asymmetric within and be¬ tween fascicles (Fig 3, Table 2). Nerve fiber changes included thinly myelinated fibers with excess Schwann cell processes, scat¬ tered fibers undergoing wallerian degenera¬ tion, and several clusters of regenerating axons.
Under
our
observation, the leg weakness
steadily progressed for 3 additional months (total length of progression, 13 months) (Fig 1, top right). Mild improvement in her strength was documented during 5 months of follow-up. Comment.—A patient with long¬ standing diabetes mellitus developed severe pain and weakness in one leg, followed 1 month later by similar symp¬ toms in the other leg. She continued to have progressive weakness for 3 months. The sural nerve biopsy speci¬ men showed asymmetric nerve fiber loss between and within fascicles. COMMENT
For many reasons, the entity re¬ ferred to as proximal diabetic neuropa-
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thy or, more often, as diabetic amy¬ otrophy deserves reappraisal. An important justification relates to the hy¬ pothesis of Asbury1' that "proximal dia¬ betic neuropathies appear to be a clini¬ cal continuum, one pole of which is represented by asymmetrical weakness of rapid evolution on an ischemie basis, with the opposite pole marked by slowly evolving symmetrical weakness due to metabolic factors." Investigators in the field were invited to test this hypothe¬ sis. We believe our patient population directly responds to this issue. Seventeen consecutive patients had a proximal neuropathy of rapid evolution with pain, weakness, and atrophy ofthe leg muscles. These cases had features similar to those described by Bruns,1 Garland and
Taverner,2''
and Raff et
al.21,22 In 16 of 17 cases, the muscle weak¬
and atrophy were asymmetric and affected both proximal and distal mus¬ cles. An important feature of our group was the documented steady or stepwise progression of weakness for 2 to 18 months. A review ofthe literature indi¬ cated that our experience demonstrat¬ ing a progressive course is not at all unique but remains an underemphasized aspect of the clinical disorder. In the 1953 report by Garland and Taverner,2 five patients were described, one of whom (case 1) had progressive weak¬ ness demonstrated during follow-up evaluations. In 1958, Sullivan" gave a detailed account of a 58-year-old man in whom weakness progressed during a 2-month period. Furthermore, in a large series reported from the Mayo Clinic,19 42 of 105 patients in whom fol¬ low-up data were available demonstrat¬ ed an average progression of 6.2 months, with variations from 1 week to more than 1 year. Another point of in¬ terest is the frequency in which both proximal and distal weakness was ob¬ served in many reports21419 of this condi¬ tion. These observations clearly demon¬ strate that patients with an abrupt onset of proximal diabetic neuropathy can have continued progression for many months. In contrast to these observations, Chokroverty et al15,26"28 provided evi¬ dence favoring a form of diabetic neu¬ ropathy with slowly evolving proximal weakness on a metabolic basis. Their observations initially focused on the analysis of data from 12 cases.26 Para¬ mount to this argument was an "insid¬ ious and slowly progressive onset" of weakness, according to the guidelines of "diabetic amyotrophy defined by Gar¬ land." Yet Garland described a syn¬ drome of asymmetric pain, weakness, muscle wasting, and areflexia,2"' which clearly should have excluded Chokroness
verty and coworkers' patient 7, a 29year-old without pain. Furthermore, another component of Chokroverty and associates' thesis, that weakness and
were maximal in the quadri¬ ceps femoris and then proceeded to the
wasting
gluteal, hamstring, adductor, and ilio-
psoas muscles, was not substantiated by serial muscle examinations. Addi¬ tional supportive evidence favoring a
metabolic insult based on electrophysio¬ logic and muscle biopsy findings includ¬ ed only nonspecific findings. The changes in the intramuscular nerves of the quadriceps did support a distal axonopathy, but unfortunately no evi¬ dence was provided that these changes were exclusive or even maximal in this site; similar findings have been de¬ scribed in the intramuscular nerves of the distal part of the legs in young dia¬ betics even without neuropathy.3637 On the basis of these studies,15,26"28 we believe the evidence is wanting that a distinct metabolic disorder preferen¬ tially affects the proximal muscles in diabetes mellitus. Another important justification for the reappraisal of this form of diabetic neuropathy relates to the names used to refer to this entity. The term diabetic amyotrophy, as coined by Garland,3" clearly provokes confusion because of
the
erroneous
primary
implications regarding a
muscle disorder. The alterna¬
tive name proposed by Asbury,17 proxi¬ mal diabetic neuropathy, has appeal be¬ cause of the importance of proximal weakness in differentiating this condi¬ tion from other types of diabetic neu¬ ropathies. On the other hand, the com¬ mon occurrence of distal weakness, as illustrated by our patients and those of others,31419,21 diminishes the preciseness of the term proximal diabetic neuropa¬ thy. For this reason, we support the use of the eponymic designation, BrunsGarland syndrome. Some will oppose this approach, but the precedent has been established and works for other disorders (eg, Guillain-Barré syn¬ drome, Emery-Dreifuss muscular dys¬ trophy) in which descriptive terms can be misleading. A final issue deserving comment re¬ lates to the pathogenesis of this disor¬ der: ischemie vs metabolic. We have al¬ ready discussed the limitations of the evidence provided that a distinct form of Bruns-Garland syndrome can be ac¬ counted for on a metabolic basis. This lack of evidence by no means indicates that an ischemie pathogenesis is estab¬ lished. On the contrary, our study ofthe sural nerve merely confirms previous reports3"'39 that this distal nerve shows
multifocal nerve fiber loss in diabetes mellitus. We also observed an increased coefficient of variation within and be¬ tween nerve fascicles. We have no way of distinguishing the changes of long¬ standing diabetes mellitus, although in two cases (patients 4 and 6; Fig 3, Table 2) the multifocal pattern of nerve fiber loss was striking despite a lack of histo¬ ry of diabetes mellitus. No morphomet¬ ric arguments, however, will prove an ischemie pathogenesis, since even in type 1 hereditary motor and sensory neuropathy, an increased coefficient of variation in the distribution of nerve fiber loss has been reported.39 In conclusion, this study emphasizes the overlap between proximal diabetic neuropathies of presumed different types. We believe our cases cast doubt that the polar types of proximal diabetic neuropathies, like the ischemie mononeuropathy multiplex of Raff et al21'22 and the proximal diabetic neuropathy of Chokroverty et al,lj26"2b are truly differ¬ ent conditions. Our series, and oth¬ ers,1419 even as far back as the original cases of Garland and Taverner,2 demon¬ strate that many patients with this syn¬ drome have a rapidly evolving disease at onset and go on to have a progressive course for many months.
References 1. Bruns L. Ueber neuritische L\l=a"\hmungenbeim diabetes mellitus. Berl Klin Wochenschr.
1890;27:509-515. 2. Garland H, Taverner D. Diabetic myelopathy. BMJ. 1953;1:1405-1408. 3. Garland H.
Diabetic
amyotrophy.
BMJ.
1955;2:1287-1290.
4. Garland H. Diabetic amyotrophy. Br J Clin Pract. 1961;15:9-13. 5. Garland H. Neurological complications of diabetes mellitus: clinical aspects. Proc R Soc Med.
1960;53:137-141. 6. Isaacs H, Gilchrist G. Diabetic amyotrophy. S Afr MedJ. 1960;34:501-505.
7. Redwood DR. Diabetic amyotrophy: imporgood diabetic control. BMJ. 1962;2:521\x=req-\ 522. 8. Locke S, Lawrence DG, Legg MA. Diabetic amyotrophy. Am J Med. 1963;34:775-785. 9. Bloodworth JMB Jr, Epstein M. Diabetic amyotrophy: light and electron microscopic investigation. Diabetes. 1967;16:181-190. 10. Hamilton CR Jr, Dobson HL, Marshall J. Diabetic amyotrophy: clinical and electronmicroscopic studies in 6 patients. Am J Med. 1968;256:81\x=req-\ 90. 11. Gregersen G. Diabetic amyotrophy: a well\x=req-\ defined syndrome? Acta Med Scand. 1969;185:303\x=req-\ 310. 12. Casey EB, Harrison MJG. Diabetic amyotrophy: a follow-up study. BMJ. 1972;1:656-659. 13. Choudhury AKR, Mukerjee AB, Choudhury NKR. Diabetic amyotrophy. J Indian Med Assoc. tance of
1973;61:37-41.
neuropathies Neurology. 1958;8:243-249. 15. Chokroverty S. Proximal nerve dysfunction in diabetic proximal amyotrophy. Arch Neurol. 14. Sullivan JF. The
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17. Asbury AK. Proximal diabetic neuropathy. Ann Neurol. 1977;2:179-180. 18. Subramony SH, Wilbourn AJ. Diabetic proximal neuropathy: clinical and electromyographic studies. J Neurol Sci. 1982;53:293-304. 19. Bastron JA, Thomas JE. Diabetic polyradiculopathy: clinical and electromyographic findings in 105 patients. Mayo Clin Proc. 1981;56:725\x=req-\ 732. 20. Bradley WG, Chad D, Verghese JP, et al. Painful lumbosacral plexopathy with elevated erythrocyte sedimentation rate: a treatable inflammatory syndrome. Ann Neurol. 1984;15:457-464. 21. Raff MC, Asbury AK. Ischemic mononeuropathy and mononeuropathy multiplex in diabetes mellitus. N Engl J Med. 1968;279:17-22. 22. Raff MC, Sangalang V, Asbury AK. Ischemic mononeuropathy multiplex associated with diabetes mellitus. Arch Neurol. 1968;18:487-499. 23. Skanse B, Gydell K. A rare type of femoralsciatic neuropathy in diabetes mellitus. Acta Med
Scand. 1956;155:463-468. 24. Goodman JI. Femoral neuropathy in relation to diabetes mellitus: report of 17 cases. Diabetes. 1954;3:266-273. 25. Calverley JR, Mulder DW. Femoral neurop-
athy. Neurology. 1960;10:963-967. 26. Chokroverty S, Reyes MG, Rubino FA, Tonaki H. The syndrome of diabetic amyotrophy. Ann Neurol. 1977;2:181-194. 27. Chokroverty S, Reyes MG, Rubino FA. Bruns-Garland syndrome of diabetic amyotrophy.
Trans Am Neurol Assoc. 1977;102:1-4. 28. Chokroverty S. AAEE case report 13: diabetic amyotrophy. Muscle Nerve. 1987;10:679-684. 29. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes.
1979;28:1039.
30. Mendell JR, Kissel JT, Kennedy MS, et al. Plasma exchange and prednisone in Guillain-Barr\l=e'\
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a controlled randomized trial. Neurology. 1985;35:1551-1555. 31. Warmolts JR, Mendell JR, O'Dorisio TM, Cataland S. Comparison of the effects of continuous subcutaneous infusion and split-mixed injection of insulin on nerve function in type 1 diabetes mellitus. J Neurol Sci. 1987;82:161-169. 32. Albers JW, Donofrio PD, McGonagle TK. Sequential electrodiagnostic abnormalities in acute
syndrome:
inflammatory demyelinating polyradiculoneuropathy. Muscle Nerve. 1985;8:528-539. 33.
MendellJR, Sahenk Z, Whitaker JN,
et al.
Polyneuropathy and IgM monoclonal gammopathy: studies on the pathogenetic role of anti-myelin\x=req-\ associated glycoprotein antibody. Ann Neurol. 1985;17:243-254. 34. Dyck PJ, Karnes J, O'Brien P, Nukada H, Lais A, Low P. Spatial pattern of nerve fiber abnormality indicative of pathologic mechanisms.
J Pathol. 1984;117:225-238. 35. Dyck PJ, Lais A, Karnes JL, O'Brien P, Rizza R. Fiber loss is primary and multifocal in sural nerves in diabetic polyneuropathy. Ann Neurol. 1986;19:425-439. 36. Reske-Nielsen E, Lundbaek K, Gregersen G, Harmsen A. Pathological changes in the central and peripheral nervous system of young long-term diabetics: the terminal neuromuscular apparatus.
Diabetologia. 1970;6:98-103. 37. Reske-Nielsen E, Gregersen G, Harmsen A, Lundbaek K. Morphological abnormalities of the terminal neuromuscular apparatus in recent juvenile diabetes. Diabetologia. 1970;6:104-109. 38. Johnson PC, Doll SC, Cromey DW. Pathogenesis of diabetic neuropathy. Ann Neurol1986;19:450-457.
39. Llewelyn JG, Thomas PK, Gibley SG, Watkins PJ, Muddle JR. Pattern of myelinated fiber loss in the sural nerve in neuropathy related to type I (insulin-dependent) diabetes. Diabetologia.
1988;31:162-167.
Syndrome (Diabetic Amyotrophy)
Revisited 100 Years Later Richard J.
Barohn, MD; Zarife Sahenk, MD; John R. Warmolts, MD; Jerry R. Mendell, MD
\s=b\ A group of 17 patients had proximal diabetic neuropathy characterized by abrupt onset of asymmetric pain and weakness. Fourteen patients had unilateral onset that later involved the other extremity in 3 days to 8 months. All patients reported stepwise or steady progression during 2 to 18 months that was documented during serial examinations. In 16 patients, both proximal and distal muscles were involved. Sural nerve biopsy specimens demonstrated multifocal variability in nerve fiber density manifesting as nonrandom fiber loss between and within fascicles compared with age-matched controls. These findings demonstrate that patients may have a rapidly evolving course of proximal diabetic neuropathy followed by continued progression for many months and emphasize the overlap between proximal diabetic neuropathies of presumed different types. Our cases and others cast doubt on notions supporting two distinct types of proximal diabetic neuropathies represented by the rapid evolution of asymmetric weakness on an ischemic basis, in contrast to a more slowly progressive condition of metabolic pathogenesis. (Arch Neurol. 1991 ;48:1130-1135)
"1 he syndrome originally described by Bruns1 and later by Garland and Taverner,2"0 who coined the term diabet¬ ic amyotrophy, continues to be a topic for debate and discussion 100 years afAccepted for publication April 15,1991.
From the Division of Neuromuscular Disease, Norman Allen Department of Neurology, Ohio State University Hospital, Columbus. Dr Barohn is now with the Division of Neurology, Department of Medicine, University of Texas Health Science Center at San Antonio. Reprint requests to Norman Allen Department of Neurology, Ohio State University Hospital, 410 W 10th Ave, Columbus, OH 43210-1228 (Dr
Mendell).
ter its
original description. These au¬ thors described a disorder character¬ ized by severe pain in the hip and thigh followed by asymmetric weakness and wasting affecting the leg muscles. Skep¬ tics originally questioned the existence of this syndrome, as reflected by Gar¬ land's0 statement before the British Royal Society of Medicine in 1960: "The reaction of others to my first paper is varied; many thought this was merely a product of my Leeds' imagination but most neurologists soon found one or more examples." A series of subsequent reports did, in fact, confirm the occur¬ rence of this entity.""14 The name diabet¬ ic amyotrophy, referring to the weak¬ ness and wasting, has proved clumsy, however, and a variety of descriptive terms have been used to refer to this disorder: diabetic proximal amy¬ otrophy,1'1 proximal diabetic neuropa¬ thy,lh"18 diabetic lumbosacral plexopathy,19-20 ischemie mononeuropathy multiplex,2122 femoral-sciatic neuropa¬ thy,23 and femoral neuropathy.24'20 An important controversy in this dis¬ ease relates to the issue of how many types of so-called diabetic amyotrophy exist. Presumably there are two dis¬ tinct disorders with different pathogen¬ ic mechanisms. Raffet al21,22 described a patient with abrupt onset of proximal and distal weakness in one leg. Evi¬ dence favoring an ischemie pathogene¬ sis was provided by an autopsy study showing infarcts of the proximal major nerve trunks of the leg and lumbosacral plexus sparing spinal roots and spinal cord. In contrast, Chokroverty et al15'26"28 emphasized an insidious, usually bilat¬ eral disorder, predominantly affecting proximal muscles due to a selective met-
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abolie insult affecting the distal branches ofthe proximal motor nerves, "a proximal intramuscular crural neu¬
ropathy."26
We studied a group of patients fulfill¬ the descriptive criteria of Bruns1 and Garland and Taverner2"0 who dem¬ onstrated an abrupt onset of pain and asymmetric weakness affecting the proximal and distal leg muscles and also exhibited subacute progression for up to 18 months. These findings suggest that presumed distinct types of proxi¬ mal diabetic neuropathies do not repre¬ sent separate, unrelated entities with different pathogenic mechanisms.
ing
PATIENTS AND METHODS
Clinical, laboratory, and biopsy results reviewed from 17 consecutive patients
were
(14 women and three men) who were exam¬ ined between January 1984 and July 1988 at the Neuromuscular Service at Ohio State University, Columbus. The diagnosis of proximal diabetic neuropathy, also referred to as diabetic lumbosacral radiculoplexopathy, was made on the basis ofthe following criteria: (1) onset of diabetes mellitus2" either before or at the onset of neurologic symp¬ toms; (2) abrupt onset of hip, back, or leg pain, either unilateral or bilateral; (3) weak¬ ness ofthe lower extremities involving proxi¬ mal muscles or proximal and distal muscles, unilaterally or bilaterally (patients with weakness confined to a peripheral-nerve dis¬ tribution were excluded); (4) results of elec¬ trophysiologic studies excluding myopathy; and (5) lumbosacral magnetic resonance im¬
computed tomograms, or myelograms excluding neoplastic disease, multiple com¬ pressive radiculopathy, and spinal stenosis. On the initial and all subsequent patient visits, manual muscle strength testing was performed on 32 muscle groups; results were graded with a modified Medical Research Council scale expanded to a 10-point system ages,
Arms
10 »
9H
Arms
10 9 8 8 co 7 ö 6
HF HA HE KE KF AD AE Al AP
1?
Legs
*
m
I
HF HA HE KE KF AD AE Al AP
o
2
< 1
0
2 4 6 8 1012141618202224
Months Arms
10 9
8
co
>
8 7 6
U o
S ;
"» CJ) Q ¿
2· < 1 0
Arms
10 9 8
Legs
: 5
4
3 S 2·
AP 10
0
Months
R
L
HF 7 HA 3 HE 2 KE10 KF 7 AD 7 AE 7 Al 7 AP 7
H
4 6 8 1012141618202224
3 3 3 3 1 0 0 0 7
2 4 6 8 1012141618202224 Months
f
CO
R_
2 4 6 8 1012141618202224 Months
matched controls. All nerve fascicles from each biopsy specimen were photographed and printed at a final magnification of 430. Each fascicle was divided into four quadrants by horizontal and vertical lines (ie, longest and shortest dimensions of an ellipsoid), and all myelinated fibers with diameters greater than 3.5 µ were counted in each quadrant. The cross-sectional area for each quadrant, as well as for the entire fascicle, was mea¬ sured by means of a visual image analyzing system (VIAS, Ted Pella Ine, Tustin, Calif). The myelinated fiber density, expressed as the number per 10,f µ 2 area for each quad¬ rant and for the whole fascicle, was plotted separately for each fascicle from patients and controls. The variability of myelinated fiber density was estimated by calculating the co¬ efficient of variation among quadrants within fascicles and between fascicles as modified from the method described by Dyck et al.34 The Wilcoxon Rank-Sum Test was done to determine the significance of nonrandom fi¬ ber distribution and loss compared with con¬ trols. In the course of this study, a total nerve area of 6.799 mm2 from patients and 2.690 mm" from controls was analyzed.
R
I8
.Arms HFHA3 _Legs HE3
5 5 2 4. 3 S, i? 2. S 1 0
KE7 KF4 AD1 AE 1 Al 1 AP2 I I I I I f f I 10 14 18 22 26 30 34 56 Months
210
8
co en
7 6
2
6
RESULTS Patient Population
The patient population included 17 patients (three men and 14 women) ranging in age from 47 to 77 years (mean± SD, 66.4 ±7.62 years). A diag¬
14 18 22 26 30 34 Months
_
Fig 1.—Course of muscle strength in six patients showing progressive leg weakness. Broken lines represent the period before the initial evaluation. Solid lines represent the course during our serial examinations. The average muscle score, shown in the table adjacent to each graph, is based on a modified Medical Research Council scale expanded to a 10-point scale (see text). The scores for leg strength are those at the nadir of the illness. R indicates right; L, left; HF, hip flexion; HA, hip abduction; HE, hip extension; KE, knee extension; KF, knee flexion; AD, ankle dorsiflexion; AE, ankle eversión; Al, ankle inversion; and AP, ankle plantar flexion.
nosis of diabetes mellitus was estab¬ lished before onset in 12 patients (71%). Three were taking insulin, six were tak¬ ing oral hypoglycémie agents, and in three the condition was controlled by diet. In five patients, a diagnosis of dia¬ betes mellitus was established coinci¬ dent with the onset of neurologic
symptoms.
Clinical Features
and summated to give an average muscle score'1" as follows: 0 was scored as 0; 1,1; 2, 2; 3-, 3; 3, 4; 3 + , 5; 4-, 4, and4 +, 7; 5-, 9; and 5, 10. Muscles tested included neck flex¬ ors, neck extensors, shoulder abductors, el¬ bow extensors, elbow flexors, wrist flexors, wrist extensors, thumb abductors, hip flex¬ ors, hip extensors, hip abductors, knee ex¬ tensors, knee flexors, ankle dorsiflexors, an¬ kle evertors, ankle invertors, and ankle plantar flexors. Eleven ofthe 17 patients had detailed follow-up at 1- or 2-month intervals. Six patients were seen initially but did not return.
Electrophysiologic Studies
Electrophysiologic studies were per¬ according to methods previously de¬
formed
scribed." Standard techniques were used for motor and sensory conduction studies by means of surface electrode recording. Electromyograms were performed on proximal and distal upper- and lower-extremity mus¬ cles. Fibrillation potentials were graded on a scale32 of 0 to 4 +, where 0 indicates no fibril¬ lations; 1 +, single persistent runs in at least two areas; 2 +, moderate numbers in three or
areas; 3 +, many fibrillations in all ar¬ eas; and 4 +, fibrillations completely filling more
the baseline.
Nerve Biopsy
Sural nerve biopsy specimens were ob¬ tained from 10 patients who were under local anesthesia, as previously described." The specimens consisted of a 4-cm segment of nerve fixed by immersion in 3% glutaraldehyde in 0.1-mol/L phosphate buffer for 30 minutes at room temperature at the in situ length. The nerve was then cut into small blocks and returned to the same fixative for an additional 2 hours, followed by postfixa¬ tion in 1% osmium tetroxide in 0.1-mol/L phosphate buffer for 2 hours. After dehydra¬ tion in graded concentrations of alcohol and propylene oxide, tissue blocks were embed¬ ded in low-viscosity embedding medium. Cross sections of nerve, 1 µ thick, were stained with toluidine blue. Morphometric analysis included assess¬ ment of myelinated nerve fiber density and the spatial pattern of nerve fiber loss be¬ tween and within nerve fascicles from biopsy specimens of 10 patients and four age-
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Pain at the onset was reported as uni¬ lateral in 14 patients and bilateral in three. At the time of initial evaluations, pain had progressed to become bilateral in all patients. In patients with unilater¬ al onset, latency to involvement of the second leg (by history) ranged from 3 days to 8 months. The pain, most severe in the back and hip, was characterized as aching, burning, and knifelike. Only seven of 17 patients complained of numbness or paresthesias in the lower extremities. By neurologic examina¬ tion, however, more patients had de¬ monstrable sensory loss in a stocking distribution. Vibratory loss was most common below the ankles and occurred in 14 patients (82%). Nine patients (53%) had decreased pin, touch, and temperature sense below the ankles. No sensory loss in a radicular or periph¬ eral-nerve distribution was observed. Muscle weakness was confined to the lower extremities. From onset until na¬ dir, all patients reported steady or step-
wise progression of weakness for 2 to 18 months (mean ± SD, 8.6 ±3.3 months). Four patients had progression for more than 1 year. In all patients, weakness was bilateral. At the initial evaluation, 16 of 17 patients exhibited asymmetric leg weakness that involved both proxi¬ mal and distal muscles. In six cases, the weakness at the hip and knee was great¬ er than that at the ankle, but in the remainder, proximal and distal muscles were equally affected. Follow-up evalu¬ ations were performed in 11 patients after 6 to 44 months (mean ± SD, 21.5 ± 13.1 months). In six patients, un¬ equivocal loss of strength occurred after the initial evaluation, as illustrated by plots of muscle strength (Fig 1). Only one of 11 patients who were followed up demonstrated a return to normal strength. Seven of 11 patients had com¬ plete resolution of pain. Tendon reflexes were absent in the lower extremities in 16 of 17 patients. In the arms, tendon reflexes were absent in five and diminished in one. Five patients reported losing sub¬ stantial amounts of weight, ranging from 13.5 to 36 kg at the time of initial evaluation.
Laboratory Studies
Fasting blood glucose levels spanned a wide range at the time of presentation (5.2 to 15.5 mmol/L), with levels above normal (>6.9 mmol/L) in 14 patients. The three patients in whom the fasting blood glucose levels were normal (5.2, 5.2, and 5.6 mmol/L) were known dia¬ betics; one was taking insulin, one was taking an oral hypoglycémie agent, and
by diet therapy. The Westergren erythrocyte sedimentation one was
treated
(normal, 2
38.2 ± 1.9t
5.6 ± 0.5
Fig 2. —Cross sections of sural nerve fascicles, 1 µ thick, from patient 4 illustrating adjacent fascicles. Nonrandom fiber loss more apparent and more severe in the left than in the right (toluidine blue, original magnification 312).
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Normal Value
SD) 4.0*
±
>5
is
9
C2
C1
C4
C3
8.
fII
6-
S5 < ja
5-
3
4.
^
3.
o
1 i'
-
'
2-
8
10
9
Patient 3.—The graph shows the myelinated fiber density (number/1 OV™2) for each quadrant (small closed circles) and for the whole fascicle in diabetic patients (patient 1 through patient 10; open circles show the fiber density for the entire fascicle) and in controls (1 through C4; large closed circles show the fiber density for each fascicle) shown at the top.
Fig
Spatial Pattern of Fiber Loss.— Morphometric studies demonstrated a significant reduction in the myelinated fiber density in all patients (3251.9 ± 1729.30/mm2; 10) com¬ with control pared subjects (7093 ± 609.07/mm2; 4). The mean fi¬ ber density for controls was comparable with previously published values.'*4 In addition, there was an increased vari¬ ability in the distribution of myelinated nerve fibers per square millimeter (Fig 3). Figure 3 shows the number of my¬ =
=
elinated fibers per 3 µ 2 for each quadrant and for the whole fascicle for patients and controls. A marked vari¬ ability in fiber density between and within fascicles was evident in all pa¬ tients, consistent with nonrandom nerve fiber loss. Patients 1, 3, 4, and 7 exhibited a greater variability than did others. The coefficient of variation was significantly different both between and within fascicles in diabetics compared with controls (P=.002 between fasci¬ cles; P= .004 within fascicles; Table 2). REPORT OF PATIENTS
The following cases reflect the clinical and pathologic spectrum of diabetic lumbosacral plexopathy observed in this group (patient numbers correspond to those in Fig 3 and Table 2).
PATIENT 4. —A 67-year-old man without a history of diabetes mellitus developed sud¬ den pain in the right thigh. Four weeks later, he experienced identical pain on the left side, accompanied by bilateral weakness. His fam¬ ily physician documented an elevated fastingblood glucose level of 13.32 mmol/L and placed him on dietary control. The Westergren erythrocyte sedimentation rate was 10 mm/h. Symptoms were accompanied by a 13.5-kg weight loss. After 4 months of pro¬ gression, resulting in difficulty in ambulation and frequent falls, the patient was referred
Table 2.—Spatial Pattern of Fiber Loss Coefficient of Within
Fasciclest Patient 1 2
3 4 5 6
to the Neuromuscular Center at Ohio State
7
University Hospitals. On neurologic examination, there was asymmetric leg weakness involving proximal and distal muscles (Fig 1, top left). A patchy loss of touch and pin sensation occurred over the thighs and lower part of the legs and did not correspond to a peripheral-nerve or ra¬
dicular distribution. Vibration sense was re¬ duced in the left foot only. Hyporeflexia was present in the arms, and tendon reflexes were absent in the legs. Peroneal motor conduction velocity was 37.8 m/s, with a distal latency of 6.1 millisec¬ onds, and amplitude was mildly reduced (1.5 mV). The sensory action potential ofthe sural nerve was unobtainable. Electromyog¬ raphy disclosed widespread fibrillation po¬ tentials (3 + to 4 + ) in the right and left proxi¬ mal and distal lower-extremity muscles. Initially only the distal part of the left leg showed denervation potentials, but during follow-up, 2 to 3 + fibrillation potentials were observed in the right anterior tibialis and
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8 9
10
0.241 0.117 0.442 0.208
0.136
Variation* Between Fascicles 0.366 0.112 0.498
0.739
0.156 0.356 0.142 0.126 0.203
0.232 0.173 0.330 0.167 0.080 0.202
0.087 0.129 0.075 0.100
0.075 0.049 0.072 0.085
Control 1
2
3 4 *
variability of myelinated fiber density was es¬ by calculating the coefficient of variation among quadrants within fascicles and between fasci¬
The timated
cles.
tAveraged values for fascicles.
gastrocnemius muscles, which had been nor¬ mal on the initial electromyographic examination. A left sural nerve biopsy specimen (Fig 2) showed nonrandom, multifocal loss of my¬ elinated nerve fibers within and between fas¬ cicles (also see data for patient 4 [Fig 3, Table 2]). Fibers in various stages of axonal degen-
eration were present. Occasional thinly my¬ elinated fibers with excessive Schwann cell processes were seen. No clusters of regener¬
ating axons were present. Clinical follow-up documented worsening for 5 additional months (total progression over 9 months), with subsequent gradual re¬ turn of strength (Fig 1, top left). Twentyfour months after onset, the patient still had considerable residual weakness. The
severe
pain had resolved, and he had persistent dull aching at night. Comment.—A
previously undiag¬
nosed diabetic developed unilateral and then bilateral leg pain and weakness in an asymmetric distribution involving proximal and distal muscles. Follow-up evaluations documented progression for 5 months. The sural nerve biopsy specimen showed a multifocal pattern of nerve fiber loss between and within fascicles. PATIENT 6.—A
58-year-old man with his¬
tory of diet-controlled diabetes mellitus de¬
veloped sudden severe back pain radiating into both legs. He noticed bilateral progres¬ sive leg weakness within days. He was re¬ ferred to the Neuromuscular Center at Ohio State University 2 months after the onset of symptoms. Neurologic examination dem¬ onstrated mildly asymmetric leg weakness involving proximal and distal muscles (Fig 1, center left). A stocking-pattern loss of pin, touch, and vibration sense was present. Ten¬ don reflexes were normal in the arms and absent in the legs. Fasting blood glucose level was mildly ele¬ vated at 8.22 mmol/L, with a normal glycosy¬ lated hemoglobin fraction of 7.0% (normal, 5.5% to 8.4%). Westergren erythrocyte sedi¬ mentation rate was 9 mm/h. The peroneal conduction velocity was mildly slow at 40 m/s, but the amplitude ofthe compound mo¬ tor action potential was significantly reduced at 300 mV. The sural nerve conduction veloc¬ ity was 38 m/s, with 5-µ" amplitude. Median and ulnar motor and sensory conduction ve¬ locities were normal. An electromyogram re¬ vealed 2 + to 3 + fibrillation potentials in the proximal and distal muscles bilaterally. A sural nerve biopsy specimen (obtained 5 months after the onset of symptoms) demonstated a nonrandom pattern of nerve fiber loss between and within fascicles, with a sig¬ nificant reduction in nerve fiber density (Fig 3, Table 2). Two months after the initial referral dem¬ onstrated more severe weakness (Fig 1, cen¬ ter left). Continued follow-up demonstrated a stepwise course with documented periods of improvement and deterioration in strength. Eleven months after the onset of symptoms, the patient's condition began to
improve steadily.
Comment.—Bilateral, asymmetric, painful, proximal and distal leg weak¬ ness developed abruptly in a known dia¬ betic. He continued to have stepwise deterioration for 11 months before sus¬ tained improvement occurred. A sural nerve biopsy specimen obtained after 5
months of progression showed a random pattern of nerve fiber loss.
non-
PATIENT 7.—A 65-year-old diabetic wom¬ treated with an oral hypoglycémie agent developed sudden severe pain in the lower part of her back that radiated to the left leg, which became weak 2 days later. After 1 month, identical pain and weakness occurred in the right leg. Symptoms persisted for 5 months, at which time an L-5 radiculopathy was diagnosed by myelography. A lumbar laminectomy was performed but did not re¬ lieve the pain or weakness. The leg symp¬ toms were accompanied by a 9-kg weight loss. Ten months after the onset, she was referred to the Neuromuscular Center at Ohio State University. On neurologic examination, asymmetric proximal and distal leg weakness was pre¬ sent with atrophy ofthe quadriceps and ham¬ string muscles, worse on the left (Fig 1, top right). A stocking-pattern loss of pin, touch, and vibration sense was present. Tendon re¬ flexes were absent at the knees and ankles. Upper extremities showed no changes in strength, reflexes, or results of sensory an
testing.
At the time of the initial evaluation, the fasting blood glucose level was 14.99 mmol/L, with an elevated glycosylated he¬ moglobin fraction of 10.3%. The Westergren erythrocyte sedimentation rate was mildly elevated at 37 mm/h. Peroneal compound mo¬ tor action potential and sural sensory poten¬
tials were unobtainable. Median motor nerve conduction was 44 m/s (normal, >48 m/s), with prolonged distal latency of 7.1 millisec¬ onds (normal, 4 mV). In the legs, denervation potentials were abundant (3+ to 4 + ) in proximal (vastus lateralis and gluteus médius) and distal (gas¬ trocnemius and anterior tibial) muscles
bilaterally.
A sural nerve biopsy specimen (obtained after 10 months of progressive symptoms) revealed a marked loss of large myelinated fibers that was asymmetric within and be¬ tween fascicles (Fig 3, Table 2). Nerve fiber changes included thinly myelinated fibers with excess Schwann cell processes, scat¬ tered fibers undergoing wallerian degenera¬ tion, and several clusters of regenerating axons.
Under
our
observation, the leg weakness
steadily progressed for 3 additional months (total length of progression, 13 months) (Fig 1, top right). Mild improvement in her strength was documented during 5 months of follow-up. Comment.—A patient with long¬ standing diabetes mellitus developed severe pain and weakness in one leg, followed 1 month later by similar symp¬ toms in the other leg. She continued to have progressive weakness for 3 months. The sural nerve biopsy speci¬ men showed asymmetric nerve fiber loss between and within fascicles. COMMENT
For many reasons, the entity re¬ ferred to as proximal diabetic neuropa-
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thy or, more often, as diabetic amy¬ otrophy deserves reappraisal. An important justification relates to the hy¬ pothesis of Asbury1' that "proximal dia¬ betic neuropathies appear to be a clini¬ cal continuum, one pole of which is represented by asymmetrical weakness of rapid evolution on an ischemie basis, with the opposite pole marked by slowly evolving symmetrical weakness due to metabolic factors." Investigators in the field were invited to test this hypothe¬ sis. We believe our patient population directly responds to this issue. Seventeen consecutive patients had a proximal neuropathy of rapid evolution with pain, weakness, and atrophy ofthe leg muscles. These cases had features similar to those described by Bruns,1 Garland and
Taverner,2''
and Raff et
al.21,22 In 16 of 17 cases, the muscle weak¬
and atrophy were asymmetric and affected both proximal and distal mus¬ cles. An important feature of our group was the documented steady or stepwise progression of weakness for 2 to 18 months. A review ofthe literature indi¬ cated that our experience demonstrat¬ ing a progressive course is not at all unique but remains an underemphasized aspect of the clinical disorder. In the 1953 report by Garland and Taverner,2 five patients were described, one of whom (case 1) had progressive weak¬ ness demonstrated during follow-up evaluations. In 1958, Sullivan" gave a detailed account of a 58-year-old man in whom weakness progressed during a 2-month period. Furthermore, in a large series reported from the Mayo Clinic,19 42 of 105 patients in whom fol¬ low-up data were available demonstrat¬ ed an average progression of 6.2 months, with variations from 1 week to more than 1 year. Another point of in¬ terest is the frequency in which both proximal and distal weakness was ob¬ served in many reports21419 of this condi¬ tion. These observations clearly demon¬ strate that patients with an abrupt onset of proximal diabetic neuropathy can have continued progression for many months. In contrast to these observations, Chokroverty et al15,26"28 provided evi¬ dence favoring a form of diabetic neu¬ ropathy with slowly evolving proximal weakness on a metabolic basis. Their observations initially focused on the analysis of data from 12 cases.26 Para¬ mount to this argument was an "insid¬ ious and slowly progressive onset" of weakness, according to the guidelines of "diabetic amyotrophy defined by Gar¬ land." Yet Garland described a syn¬ drome of asymmetric pain, weakness, muscle wasting, and areflexia,2"' which clearly should have excluded Chokroness
verty and coworkers' patient 7, a 29year-old without pain. Furthermore, another component of Chokroverty and associates' thesis, that weakness and
were maximal in the quadri¬ ceps femoris and then proceeded to the
wasting
gluteal, hamstring, adductor, and ilio-
psoas muscles, was not substantiated by serial muscle examinations. Addi¬ tional supportive evidence favoring a
metabolic insult based on electrophysio¬ logic and muscle biopsy findings includ¬ ed only nonspecific findings. The changes in the intramuscular nerves of the quadriceps did support a distal axonopathy, but unfortunately no evi¬ dence was provided that these changes were exclusive or even maximal in this site; similar findings have been de¬ scribed in the intramuscular nerves of the distal part of the legs in young dia¬ betics even without neuropathy.3637 On the basis of these studies,15,26"28 we believe the evidence is wanting that a distinct metabolic disorder preferen¬ tially affects the proximal muscles in diabetes mellitus. Another important justification for the reappraisal of this form of diabetic neuropathy relates to the names used to refer to this entity. The term diabetic amyotrophy, as coined by Garland,3" clearly provokes confusion because of
the
erroneous
primary
implications regarding a
muscle disorder. The alterna¬
tive name proposed by Asbury,17 proxi¬ mal diabetic neuropathy, has appeal be¬ cause of the importance of proximal weakness in differentiating this condi¬ tion from other types of diabetic neu¬ ropathies. On the other hand, the com¬ mon occurrence of distal weakness, as illustrated by our patients and those of others,31419,21 diminishes the preciseness of the term proximal diabetic neuropa¬ thy. For this reason, we support the use of the eponymic designation, BrunsGarland syndrome. Some will oppose this approach, but the precedent has been established and works for other disorders (eg, Guillain-Barré syn¬ drome, Emery-Dreifuss muscular dys¬ trophy) in which descriptive terms can be misleading. A final issue deserving comment re¬ lates to the pathogenesis of this disor¬ der: ischemie vs metabolic. We have al¬ ready discussed the limitations of the evidence provided that a distinct form of Bruns-Garland syndrome can be ac¬ counted for on a metabolic basis. This lack of evidence by no means indicates that an ischemie pathogenesis is estab¬ lished. On the contrary, our study ofthe sural nerve merely confirms previous reports3"'39 that this distal nerve shows
multifocal nerve fiber loss in diabetes mellitus. We also observed an increased coefficient of variation within and be¬ tween nerve fascicles. We have no way of distinguishing the changes of long¬ standing diabetes mellitus, although in two cases (patients 4 and 6; Fig 3, Table 2) the multifocal pattern of nerve fiber loss was striking despite a lack of histo¬ ry of diabetes mellitus. No morphomet¬ ric arguments, however, will prove an ischemie pathogenesis, since even in type 1 hereditary motor and sensory neuropathy, an increased coefficient of variation in the distribution of nerve fiber loss has been reported.39 In conclusion, this study emphasizes the overlap between proximal diabetic neuropathies of presumed different types. We believe our cases cast doubt that the polar types of proximal diabetic neuropathies, like the ischemie mononeuropathy multiplex of Raff et al21'22 and the proximal diabetic neuropathy of Chokroverty et al,lj26"2b are truly differ¬ ent conditions. Our series, and oth¬ ers,1419 even as far back as the original cases of Garland and Taverner,2 demon¬ strate that many patients with this syn¬ drome have a rapidly evolving disease at onset and go on to have a progressive course for many months.
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