Dear Sirs,
Peripheral neuropathy is an important complication of diabetes mellitus. A particular
type of proximal diabetic neuropathy, lumbosacral radiculoplexus neuropathy (DLSRPN),
presents with pelvi-femoral pain followed by weakness, beginning focally in the upper
leg or thigh with spread to the contralateral limb, and variable weight loss [1].
Ischemic nerve injury due to microscopic vasculitis has been a widely postulated unifying
hypothesis of DLSRPN and derived from one well studied postmortem case reported 4 decades
ago, the finding of microscopic vasculitis in proximal or distal cutaneous nerve biopsy
tissue and the favorable response to immunotherapy.
A 59 year old man with diabetes mellitus for 15 years treated with oral hypoglycemic
medication noted left thigh pain, paresthesia, and impotence commencing in January
1995. This was followed by sensory changes and weakness first in the left leg then
in the other in a stepwise fashion leading first to the necessity of a cane, then
walker accompanied by a 15 lb weight loss, until he was essentially bed-bound and
admitted to the hospital in June 1995. Admission neurological examination showed wasting
and near-flail weakness in the legs from the thighs to the toes with rare limb fasciculation,
mild distal weakness of the hands in the distribution of the distal median and ulnar
nerves, mild stocking sensory loss to light touch, vibratory and cold temperature
stimulation to just above the knee, areflexia, and otherwise intact cranial nerves
and cognition.
Admission laboratory studies showed erythrocyte sedimentation rate 60 mm/hour (normal
<20), fasting blood glucose 250 mg/dL (normal <105), and hemoglobin A1C level 7.1%
(normal <6). Causes of neuropathy other than diabetes mellitus were excluded by appropriate
investigations. Nerve conduction studies and electromyography (EMG) of the right arm
and leg showed axonal neuropathy with acute and chronic denervation in proximal and
distal limb muscles including lumbosacral paraspinal muscles. Cerebrospinal fluid
showed total protein 122 mg/dL (normal <45) and glucose 88 mg/dL with 12 white blood
cells/mm3 (normal <5). Right sural nerve biopsy showed features of microvasculitis
(MV). Inflammatory cells surrounded a small epineurial artery with extension into
the vascular wall, with reactive luminal connective tissue suggesting recanalization
of a thrombus. An adjacent nerve fascicle showed marked loss of myelinated nerve fibers.
The patient was treated for painful diabetic lumbosacral plexopathy and peripheral
nerve vasculitis according to prevailing standards with 2 g/kg intravenous immunoglobulin
for 5 days, followed by 750 mg of intravenous cyclophosphamide and 1,000 mg of methylprednisolone
intravenously for 3 additional days. This was followed by acute tubular necrosis,
increasing lethargy, unresponsiveness, and aspiration pneumonia requiring mechanical
ventilation. He expired 4 weeks after admission.
General autopsy showed no evidence of systemic or peripheral nerve vasculitis. The
brain showed diffuse loss of neurons in all sampled cortical areas, including the
cerebellum, consistent with anoxia secondary to cardiac arrest. Sections of extradural
lumbar plexus, sciatic, and femoral nerve tissue showed perivascular epineurial inflammation
with infiltration of adjacent endoneurium (Fig. 1a, b).
Fig. 1
Postmortem histopathology. a Transverse section of the left sciatic nerve shows perivascular
chronic inflammation surrounding small blood vessels of the epineurium. b Transverse
section of the left femoral nerve in addition shows perivascular chronic inflammation
in the subperineurial area. Inflammatory cells infiltrate the adjacent endoneurium
(Paraffin, H&E, 200X)
Perivascular inflammation, not MV, was noted in postmortem nerve tissue in our patient.
Although the significance of our findings is not well understood, they do suggest
the contribution of vascular autoimmune factors in the etiopathogenesis of DLSRPN,
but do not provide clear evidence of ischemic nerve injury due to microscopic vasculitis
in this disorder.
The history of DLSRPN embodies more than a century of insights into proximal diabetic
neuropathy (PDN), diabetic amyotrophy, and peripheral nerve vasculitis. An ischemic
etiopathogenesis of DLSRPN was first suggested by Raff and colleagues [2] in a newly
diagnosed non-insulin dependent diabetic with mononeuritis multiplex presenting with
acute asymmetrical leg pain and weakness, bilateral distal sensory disturbances, and
reduced leg reflexes. Postmortem examination showed a multitude of unilateral small
ischemic infarctive lesions of the proximal major nerve trunks of the leg and lumbosacral
plexus.
Further proof of the ischemic inflammatory basis of DLSRPN stemmed from analysis of
proximal and distal cutaneous nerve biopsy. In 1984, Bradley and coworkers [3] delineated
the syndrome of painful lumbosacral plexopathy with elevated erythrocyte sedimentation
rate among six patients, three of whom were diabetic including one newly diagnosed,
with perivasculitis (PV) in sural nerve biopsies. In the same period, Johnson and
coworkers [4] noted focal fascicular lesions distributed in proximal lumbosacral plexus
trunks of 18/32 samples obtained at autopsy from diabetic patients, a quarter of whom
were insulin-dependent, without mononeuritis multiplex employing epoxy-embedded and
teased nerve fiber sections. These findings suggest a possible propensity for the
spontaneous evolution of DLSRPN in patients with diabetic neuropathy. A decade later,
Said and coworkers [5] studied 10 non-insulin dependent diabetics with painful PDN
and reported ischemic nerve lesions due to arteritis in three biopsies of the intermedius
cutaneous nerve of the thigh, and four others with isolated mononuclear cell inflammation.
One year later, Krendel and associates [6] identified 5 of 15 non-insulin dependent
diabetics with progressive proximal asymmetric neuropathy progressing over 1–15 months
punctuated by pain, weakness, and atrophy of one thigh, followed by involvement of
the contralateral extremity in 2–10 weeks. Biopsy of the cutaneous branch of the femoral
nerve in one patient showed epineurial PV, while sural nerve tissue in another had
microfasciculation that was postulated to result from regeneration after nerve infarction.
In 1996, Younger and colleagues [7] characterized the vascular endoneurial and epineurial
inflammatory lesions among 12 patients with stepwise or slowly progressive proximal
weakness, wasting, and pain, and axonopathy on electrodiagnostic studies indicative
of DLSRPN. Six nerves showed epineurial MV and six had epineurial PV comprised of
cytotoxic/suppressor T cells with activated endoneurial lymphocytes that expressed
immunoreactive cytokines, major histocompatibility class II antigens, endoneurial
and epineurial C3d and C5b-9 complement. The nerve tissue of two patients with MV
in addition had focal pathology indicative of ischemia. In 1998, Llewelyn and colleagues
[8] studied 15 patients including one with insulin-dependent diabetes and PDN manifested
by subacute asymmetric pain, weakness, and wasting of the legs. Epineurial MV was
noted in three of 15 femoral intermedius cutaneous nerve biopsies comprised of helper
T cells and cytotoxic/suppressor T and B cells, with a single occluded vessels in
two, and T cell MV in the sural nerve and vastus lateralis muscle of the another patient.
Dyck and colleagues [9] later reported perivascular inflammation in all 33 distal
cutaneous nerves in DLSRPN, 15 (45%) of which infiltrated the vessel wall, and MV
in two nerves with histological features of ischemic nerve injury. One year later,
Kelkar and colleagues [10] described 16 patients with PDN and EMG findings of acute
spontaneous activity in two proximal leg muscles innervated by different nerves, including
but not limited to paraspinal muscles indicative of DLSRPN; all were non-insulin dependent,
with functional impairment that varied from three patients who were wheelchair bound,
four necessitating a walker, and eight patients requiring support of a cane to ambulate
at presentation. Fourteen patients underwent femoral cutaneous nerve biopsy and two
underwent sural nerve biopsy. Nerve biopsy pathology showed epineurial MV comprised
of polymorphonuclear cells in postcapillary venules of the femoral cutaneous nerve
in four patients, and lymphocytic MV of the sural nerve of six patients, including
one nerve with occlusion and recanalization of an epineurial vessel. There was binding
of immunoreactive IgM and activated complement protein in the subperineurial space
and endoneurium consistent with immune-mediated ischemic injury.
The past 3 decades have witnessed a critical appraisal of the immunotherapeutic management
of DLSRPN. Bradley and coworkers [3] administered corticosteroids ranging from 60 mg
daily to 80 mg of alternate day prednisone alone in one patient, and in association
with cyclophosphamide 100 mg daily in two others, with improvement over 6 weeks often
with a decrease in the erythrocyte sedimentation rate. A decade later the same authors
[11] treated the disorder with 2 g/kg body weight of intravenous immune globulin (IVIg)
over 5 days followed by single monthly treatments for 3 months, the endpoint of which
was improved Medical Research Council (MRC) graded strength that enabled ambulation.
In the same year, 1995, Said and colleagues [5] treated two of 10 affected patients
with prednisone 1 mg/kg/day for 6 weeks prompted by the presence of lymphocytic vasculitis
in epineurial blood vessels with asymmetrical nerve lesions and centrofascicular axonal
loss along the intermedius nerve of the thigh in one, and another with occlusion of
a perineurial blood vessel and a small mononuclear inflammatory cell infiltrate along
the superficial sensory branch of the peroneal nerve. Both patients had improved pain
along with corticosteroid induced hyperglycemia, including one patient with a gastric
ulcer. Seven additional patients, all without vasculitis improved spontaneously. Krendel
and coworkers [6] treated five affected patients with IVIg alone in one patient, in
combination with 60 mg of prednisone in 3 patients, or with 1 g of intravenous cyclophosphamide
in another. All five patients stopped progressing after commencing therapy and gained
at least 1 grade of the MRC scale.
Most recently, Dyck and colleagues [9, 12] noted equally significant objective improvement
in primary outcome measures of 49 patients with DLSRPN randomized to 1 g 3 times weekly
of intravenous methylprednisolone for 12 weeks, compared to 26 patients with DLSRPN
who received placebo when analyzed at 52 [12] and 104 weeks [9]. However, the methylprednisolone
treated patients reported a greater degree of symptom improvement as judged by changes
in a neuropathy symptom change subscore for pain. A randomized, double-blind placebo-controlled
trial of IVIg on recovery time of patients with PDN and EMG evidence of proximal lower
limb plexus or radicular denervation that commenced in 1999 [13] is still ongoing
but no longer recruiting study participants, and has yet to publish its findings.
In summary, DLSRPN is a well recognized, painful, asymmetrical, immune mediated neuropathy
of the lower limbs associated generally with non-insulin dependent diabetes, weight
loss, and significant morbidity. The disorder has evolved along different nomenclature
and eponymic terminology reflecting the diversity in opinions concerning the anatomic
localization and underlying etiopathogenesis. The clinicopathological findings in
the present patient were consistent with a mechanism of ischemic nerve injury due
to microscopic vasculitis. Neurologists faced with the challenge of treating DLSRPN
must choose from among available immune mediated interventions, weighing the inherent
risks, benefits, and anticipated efficacy, and tailored to the clinical, electrophysiological,
and cutaneous nerve biopsy findings to optimize recovery and forestall severe neurological
disability.