Diabetic Cervical Radiculoplexus Neuropathy

weakness and spread to unaffected segments and other body re-

gions. The CSF protein was elevated in both, suggesting that the

pathological process extended to the root level. Paraspinal muscle

involvement on EMG was further evidence of root involvement in

both DCRPN and DLRPN. As in DLRPN, the nerve conduction

studies/EMG and quantitative sensory and autonomic testing con-

firmed patchy but widespread involvement of motor, sensory and

autonomic nerves of all fibre classes (large and small myelinated

Figure 2 Evidence for focal nature of microvasculitis in DCRPN. Serial paraffin sections (AF) showing microvasculitis (top row) withvessel wall destruction and muscle fragmentation (B) but no inflammation on a distal section of the same epineurial blood vessel (middle

row). Another epineurial blood vessel from a different patient showing also microvasculitis (GI). Note the separation and destruction of

the vessel wall by inflammation in both vessels. (A, D and G) Haematoxylin and eosin; (B, E and H) smooth muscle actin immunostaining;

(C, F and I) CD-45 (leukocyte common antigen) immunostaining.

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and unmyelinated) resulting from a non-length-dependent neuro-

pathic axonal injury. Mild differences were found which may be

due to the DCRPN cohort being more mildly affected than

DLRPN. Our inclusion criteria may have partially explained this

difference as in our DLRPN cohort we insisted that two nerves

from two different nerve root distributions were involved whereas

in DCRPN we allowed upper limb mononeuropathies. We believed

that it was best to include diabetic mononeuropathies because

non-diabetic neuralgic amyotrophy is recognized to sometimes

present as mononeuropathies. Both syndromes started unilaterally

and both frequently progressed to bilateral disease. Overall, pa-

tients with DCRPN eventually developed less contralateral involve-

ment than patients with DLRPN did, but they commonly had

widespread involvement of other regions. The neuropathy in

DCRPN presented more acutely and, while still causing significant

morbidity, also improved more quickly than in DLRPN (on first

follow-up, the neuropathy impairment score generally improved

in DCRPN but not in DLRPN). Although pain was the most

common presenting symptom, some patients with DCRPN re-

ported no upper extremity pain which is likely to be due to in-

volvement of focal motor nerves (anterior inter-osseous, axillary,

phrenic and long thoracic).

Perhaps the most striking similarity between the two syndromes

was the neuropathological abnormalities. In both disorders, there

was evidence of ischaemic injury (active axonal degeneration,

multifocal fibre loss, injury neuroma, focal perineurial thickening

and neovascularization) and of microvasculitis (hemosiderin depos-

ition, epineurial perivascular and vessel wall inflammation and

diagnostic changes of microvasculitis). In our DCRPN cohort,

upper limb biopsies showed more striking changes than lower

limb biopsies (even though they had concomitant DLRPN) and

all cases diagnostic of microvasculitis were in upper limb biopsies.

This observation is likely to be due to the fact that our patients

with DCRPN were selected for their upper limb involvement and

so the upper limb syndrome was the most active neuropathic pro-

cess in these patients. Ischaemic injury and microvasculitis has

been described in DLRPN previously but not in DCRPN (Said

et al., 1994; Llewelyn et al., 1998; Dyck et al., 1999, 2000;

Kelkar et al., 2000). This finding of similar pathology between

the upper and lower limb forms supports a common disease mech-

anism between DLRPN and DCRPN.

In addition to these many similarities, the frequent co-

occurrence of thoracic (DTRPN) and lumbosacral (DLRPN) involve-

ment in our patients with DCRPN, as well as the frequent

co-occurrence of DCRPN in patients presenting as DLRPN (Dyck

et al., 1999; Katz et al., 2001) strongly argue in favour of a

common underlying mechanism and for classifying these disorders

together as diabetic radiculoplexus neuropathies. Analysis of our

isolated DCRPN cohort showed that they were similar in terms of

their glucose characteristics and neuropathy presentation and def-

icits to the patients with DCRPN with more widespread involve-

ment (co-existing cranial, thoracic and lumbosacral disease),

confirming that DCRPN should be viewed as part of the diabetic

radiculoplexus neuropathy spectrum. Furthermore, of the 20 pa-

tients with both DCRPN and DLRPN, 15 of them predominantly

involved the upper limb providing evidence that DCRPN should

Figure 3 Axonal degeneration, multifocal fibre loss and evidence of previous bleeding in DCRPN. (A) Teased fibre preparation showingmultiple strands with fulminant early axonal degeneration. (B) Low and (D) higher power methylene blue epoxy section of nerve

illustrating multifocal inter- and intrafascicular fibre loss. (C) Longitudinal paraffin section showing hemosiderin deposition (blue discol-

ouration) in the vessel wall, evidence of previous bleeding.

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Figure 4 Evidence of concomitant necrotizing vasculitis and microvasculitis involving medium- and small-vessels in DCRPN from theillustrative case (see text). Longitudinal section showing fibrinoid necrosis (arrows A and B) and necrotizing vasculitis of a medium vessel

(A, B and C) and microvasculitis (lower right vessel in A, D and E) in the same nerve field (illustrative case). (A and D) Haematoxylin and

eosin; (B) Masson trichrome; (C and E) CD-45 (leukocyte common antigen) immunostaining.


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not be viewed as a spill-over of the DLRPN disease process.

Overall, these conditions represent different presentations of the

same pathophysiological entity with variable geographic manifest-

ations in the PNS (cranial, cervical, thoracic and lumbosacral).

Our study has certain limitations. The retrospective nature of

the chart review limits the applicability of the data. Several pa-

tients were excluded because of lack of essential information

(including a detailed neurological examination). All included pa-

tients were seen by a Mayo clinic neurologist (n = 84) or physiat-

rist (n = 1), and 53/85 were seen by a neuromuscular specialist.

Another limitation is that Mayo clinic is a quaternary centre, which

makes a referral bias towards more complicated cases likely.

Nonetheless, 14/85 patients were from Olmsted County (the

local community), suggesting that this disorder is not very rare.

Some authors have suggested that brachial plexopathies in dia-

betic patients is merely a chance occurrence (Wilbourn, 1999).

While we agree that this may be true in some cases, and that

to answer this question definitively, large epidemiological studies

would need to be done, we strongly believe that the frequent

co-occurrence of different forms of diabetic radiculoplexus neuro-

pathies together with associated weight loss is compelling evi-

dence for a common pathological mechanism and an association

with diabetes mellitus. Therefore, we conclude that DCRPN is

likely to be a distinct disease entity that is part of the spectrum

of diabetic radiculoplexus neuropathies.

We speculate that diabetes mellitus is one of perhaps several

risk factors that predisposes patients to altered immunity leading

to an auto-immune attack on the nerve small blood vessels. Other

possible risk factors include starting treatment for hyperglycaemia,

immunization, infectious illness or having a surgical procedure per-

formed. It is noteworthy that 20 of the 85 patients were diag-

nosed with diabetes mellitus within a year of their developing

DCRPN and most of these had concomitant initiation of insulin

or oral hypoglycaemic treatment, which could have acted as a

trigger to this immune deregulation (Gibbons and Freeman,

2010). The various positive inflammatory and rheumatological

markers are also consistent with an alteration in the immune

system. The majority of patients (49/85) reported a potential

immune trigger (10 post-viral/systemic illness, three post-

vaccination, 26 post-surgical procedures and nine after minor

trauma or heavy exercise) to the DCRPN episode. The frequent

preceding surgeries before the development of DCRPN suggest

that a surgical procedure may constitute an important risk

factor/trigger in addition to diabetes mellitus itself in leading to

an inflammatory plexus neuropathy. This position is supported by

the observation that one-third of patients with post-surgical in-

flammatory neuropathy previously described were also diabetic

(Staff et al., 2010). The possible improvement with immunother-

apy would also suggest a role of altered immunity and implies that

early treatment may be beneficial. While further randomized con-

trolled trials would be needed, the pathological alterations of

microvasculitis may favour using high-dose steroids at the onset

of pain and weakness, over other immune treatments (such as

intravenous immunoglobulin) (Gorson, 2006).

Previous studies (Parsonage and Turner, 1948; Tsairis, et al.,

1972; England and Sumner, 1987) have examined an upper limb

immune-mediated plexus neuropathy in non-diabetic patients,

with the largest one (van Alfen and van Engelen, 2006) investigat-

ing 246 Dutch patients with detailed description of their clinical

presentation and evolution. Our patients are generally distinct

from patients with idiopathic and hereditary neuralgic amyotrophy

by their autonomic features, more frequent weight loss, common

bilateral upper limb and lower trunk involvements, and

co-occurring thoracic and lumbosacral radiculoplexus neuropa-

thies. Specifically, compared to the van Alfen and van Engelen,

2006 series, our patients had more involvement outside of the

brachial plexus (38% versus 17%) and had more involvement of

the lower trunk of the brachial plexus (58% versus 4%). More

patients experienced weight loss in our group (35% versus 20%)

and almost all had evidence of autonomic dysfunction. The degree

of autonomic involvement was more than would be expected

from the degree of glucose dysregulation and is typical of other

diabetic radiculoplexus neuropathies (Dyck et al., 1999). In the

van Alfen series, diabetes mellitus was not felt to be more repre-

sented in those with idiopathic or inherited brachial plexus neuro-

pathies compared to the general population, but of their six

patients with diabetes mellitus, four had recurrent attacks.

As in DLRPN, the findings on clinical examination were more

focal than those on neurophysiology and nerve imaging, which

tended to be much more widespread. The imaging findings are

particularly important. Few MRI descriptions of inflammatory neu-

ropathies exist as most MRI series of non-traumatic brachial plexo-

pathies (Wittenberg and Adkins, 2000; Mullins et al., 2007) have

a limited number of inflammatory cases. When reviewed by a

peripheral nerve radiologist, abnormalities were noted in all pa-

tients with DCRPN in our study (38/38). While MRI has been

traditionally performed to rule out neoplastic or other compressive

lesions, these findings reinforce its role as a potential diagnostic

confirmatory test in inflammatory disease. We have found

increased T2 signal to be the most sensitive abnormality, being

present in 45 of 47 MRIs. Although less frequent, changes in

muscle signal were also important as they helped discriminate be-

tween an acute or subacute denervating process (increased T2signal secondary to oedema) versus a more chronic process

(increased T1 signal secondary to fatty atrophy).

Herein, we describe diabetic patients with acute to subacute

painful and paralytic upper limb neuropathies in terms of clinical,

laboratory and pathological features and conclude that they have

DCRPN. We have shown that our DCRPN cohort shares many of

the same features as a DLRPN cohort and that both are due to

ischaemic injury, frequently from microvasculitis. We have found

that the upper limb, lower limb and truncal syndromes often occur

together. Therefore, we propose that DCRPN, diabetic thoracic

radiculoneuropathies and DLRPN are part of a more diffuse spec-

trum disorder of diabetic radiculoplexus neuropathies. Their

common co-occurrence along with their association with diabetes

mellitus would suggest that diabetes is a strong risk factor in their

pathogenesis. Identification of DCRPN expands the PNS compli-

cations of diabetes mellitus.

FundingMayo Clinic Foundation.

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