Non-Systemic Vasculitic Neuropathy: An Enigmatic Clinical Entity.

BACKGROUND: Non-systemic vasculitic peripheral neuropathy is a rare condition characterized by necrotizing inflammation resulting in luminal narrowing of the vasa nervorum, leading to ischemic injury to peripheral nerves. Here, we present the case of 63-year-old woman with subacute onset of severe hyperesthesia of the lower extremities accompanied by foot drop. CASE REPORT: A 63-year-old woman with prolonged history of uncontrolled diabetes mellitus presented with subacute onset of severe bilateral lower extremity hyperesthesia and motor weakness along with left-sided foot drop. She had multiple emergency room visits with no relief of her symptoms. High doses of analgesics were insufficient to control pain. Laboratory tests were positive only for high erythrocyte sedimentation rate and C-reactive protein. A skin biopsy obtained 5 cm above the left lateral malleolus revealed medium-sized dermal vasculitis with dense mononuclear infiltrate. Electromyography showed peripheral neuropathy. A nerve biopsy was needed to reveal the exact diagnosis. CONCLUSIONS: Diagnosis of non-systemic vasculitic peripheral neuropathy can be delayed or missed in patients with uncontrolled diabetes mellitus, leading to significant morbidity. Elevated markers of inflammation in the absence of a possible explanation should prompt the clinician to perform a nerve biopsy; however, it is an invasive procedure and is associated with complications of post-neuropathic pain and delayed wound healing. Magnetic resonance angiography of the lower limbs, if combined with skin biopsy, can save the patient from undergoing nerve biopsy.

Strength and balance training for adults with peripheral neuropathy and high risk of fall: current evidence and implications for future research.

PURPOSE/OBJECTIVES: To evaluate the evidence for strength- and balance-training programs in patients at high risk for falls, discuss how results of existing studies might guide clinical practice, and discuss directions for additional research. DATA SOURCES: A search of PubMed and CINAHL® databases was conducted in June 2011 using the terms strength, balance training, falls, elderly, and neuropathy. Only clinical trials conducted using specific strength- or balance-training exercises that included community-dwelling adults and examined falls, fall risk, balance, and/or strength as outcome measures were included in this review. DATA SYNTHESIS: One matched case-control study and two randomized, controlled studies evaluating strength and balance training in patients with diabetes-related peripheral neuropathy were identified. Eleven studies evaluating strength and balance programs in community-dwelling adults at high risk for falls were identified. CONCLUSIONS: The findings from the reviewed studies provide substantial evidence to support the use of strength and balance training for older adults at risk for falls, and detail early evidence to support strength and balance training for individuals with peripheral neuropathy. IMPLICATIONS FOR NURSING: The evidence demonstrates that strength and balance training is safe and effective at reducing falls and improving lower extremity strength and balance in adults aged 50 years and older at high risk for falls, including patients with diabetic peripheral neuropathy. Future studies should evaluate the effects of strength and balance training in patients with cancer, particularly individuals with chemotherapy-induced peripheral neuropathy.

The vasculitic neuropathies: an update.

PURPOSE OF REVIEW: Vasculitic neuropathy is a heterogeneous disorder that usually occurs in systemic diseases, but less commonly appears as nonsystemic vasculitic neuropathy (NSVN). This review is intended to highlight recent developments in the field of vasculitic neuropathies. RECENT FINDINGS: A Peripheral Nerve Society guideline provides data-driven consensus recommendation on classification of vasculitic neuropathies and diagnosis/treatment of NSVN. NSVN is sometimes accompanied by subclinical inflammation of adjacent skin. Amyotrophic lateral sclerosis with sensory involvement can mimic NSVN. Systemic vasculitides with neuropathy include polyarteritis nodosa, microscopic polyangiitis (MPA), rheumatoid vasculitis, Churg-Strauss syndrome (CSS), and hepatitis C-related mixed cryoglobulinemic vasculitis (MCV). At autopsy, MPA affects limb nerves diffusely, with maximal damage in proximal/middle segments. CSS can be accompanied by antineutrophil cytoplasmic antibodies (ANCAs), but most patients with neuropathy lack ANCAs. Cryoglobulinemic neuropathies are usually caused by vasculitis, irrespective of phenotype. Two randomized trials revealed rituximab to be noninferior to cyclophosphamide for inducing remission in ANCA-associated vasculitis. Many reports also document efficacy of rituximab in MCV. SUMMARY: Consensus guidelines on NSVN should be evaluated prospectively. MPA-associated vasculitic neuropathy results from vasculitic lesions distributed diffusely throughout peripheral extremity nerves. Rituximab is effective for ANCA-associated and cryoglobulinemic vasculitis with neuropathy.

Bone marrow mononuclear cells have neurovascular tropism and improve diabetic neuropathy.

Bone marrow-derived mononuclear cells (BMNCs) have been shown to effectively treat ischemic cardiovascular diseases. Because diabetic neuropathy (DN) is causally associated with impaired angiogenesis and deficiency of angiogenic and neurotrophic factors in the nerves, we investigated whether DN can be ameliorated by local injection of BMNCs. Severe peripheral neuropathy, characterized by a significant decrease in the motor and sensory nerve conduction velocities (NCVs), developed 12 weeks after the induction of diabetes with streptozotocin in rats. The injection of BMNCs restored motor and sensory NCVs to normal levels and significantly improved vascular density and blood flow in diabetic nerves over 4 weeks. Fluorescent microscopic observation revealed that DiI-labeled BMNCs preferentially engrafted in sciatic nerves. Whole-mount fluorescent imaging and confocal microscopic evaluation demonstrated that many of the BMNCs localized following the course of the vasa nervorum in close proximity to blood vessels without incorporation into vasa nervorum as endothelial cells at a detectable level. Real-time reverse transcription-polymerase chain reaction analysis showed that the levels of angiogenic and neurotrophic factors were significantly increased in the nerves by BMNC injection. Local transplantation of BMNCs improved experimental DN by augmenting angiogenesis and increasing angiogenic and neurotrophic factors in peripheral nerves. These findings suggest that BMNC transplantation may represent a novel therapeutic option for treating DN.

Morphological and ultrastructural analysis of the watershed zones after stripping of the vasa nervorum.

Peripheral nerve trunks are well-vascularized structures where a well-developed collateral system may compensate for local vascular damage. Vasculitis in nerve has a predilection for epineurial vessels and causes to the peripheral neuropathy, which is a major clinical feature of primary and secondary systemic vasculitides. In the present study, the goal was to simulate the vasculitic neuropathy in rat sciatic nerve and to investigate the watershed zones after stripping of the epineural vessels of the sciatic nerve. Sciatic function index values, light and electron microscopic evaluations of the experimental sciatic nerve suggested that the sciatic nerve was normal except for some watershed zones located in the peripheral part of the nerve. Although there is abundant collateral circulation in the peripheral nerve, distribution of the vessels of the watershed zones as observed in the present study should be elucidated by further studies.

Objective assessment of the perineural vascular plexus as a landmark for the horizontal part of the facial nerve in middle ear and mastoid surgery.

OBJECTIVE: To objectively evaluate the usefulness and the reliability of the perineural vascular plexus as a landmark for identification of the facial nerve in surgery for chronic squamous otitis media. STUDY DESIGN: Prospective case series. SETTING: Tertiary otologic center. PATIENTS: Seventy consecutive patients requiring surgery for cholesteatomatous otitis media. INTERVENTION: Use of a semiquantitative grading system intraoperatively to assess the utility and ease of using the perineural facial plexus as the pointer to the facial nerve. MAIN OUTCOME MEASURES: Description of the perineural vascular plexus and assessment of the reproducibility of the grading system. RESULTS: In 82.5% of patients, the plexus was used as the sole pointer to the level of the facial nerve, with other landmarks being used in the remaining 17.5%. A very prominent vessel was used to identify the nerve in 82.5%, therefore being classified as Grade 1. Multiple small vessels were seen in 15.8% (Grade 2), and in 1.5% the vessel plexus was thin and difficult to identify. The average measure intraclass correlation was 0.75 (95% confidence interval, 0.57-0.85), indicating excellent reproducibility of the system. CONCLUSION: We believe that the perineural vascular plexus is a dependable and reliable landmark for the level of the facial nerve in surgery for chronic otitis media.

Sonic hedgehog induces arteriogenesis in diabetic vasa nervorum and restores function in diabetic neuropathy.

OBJECTIVE: The embryonic morphogen sonic hedgehog (SHh) has been shown to induce neovascularization of ischemic tissue but has not been shown to play a role in regulating vascular nerve supply. Accordingly, we investigated the hypothesis that systemic injection of SHh protein could improve nerve blood flow and function in diabetic neuropathy (DN). METHODS AND RESULTS: Twelve weeks after induction of diabetes with streptozotocin, motor and sensory nerve conduction velocities (MCV and SCV) of the sciatic nerves were significantly reduced in diabetic rats. SHh-treated diabetic rats demonstrated marked improvement of both MCV and SCV (P<0.05). Laser Doppler perfusion imaging showed that nerve blood flow was significantly reduced in the diabetic rats but was restored in SHh-treated diabetic rats (P<0.05 versus diabetic saline-treated rats) to levels similar to those achieved with vascular endothelial growth factor-2 (VEGF-2) gene therapy. In vivo perfusion of Bandeuraea simplicifolia (BS)-1 lectin showed marked reduction in the vasa nervora in diabetic sciatic nerves but restoration of nerve vasculature to nondiabetic levels in the SHh-treated and plasmid DNA encoding human VEGF-2 (phVEGF-2)-treated diabetic nerves. Interestingly, the SHh-induced vasculature was characterized by larger diameter and more smooth muscle cell-containing vessels, compared with VEGF-2 gene-treated diabetic rats. CONCLUSIONS: These data indicate that Shh induces arteriogenesis and restores nerve function in DN.

Asthma associated with worsening leg ulcer: a case of vasculitis in primary care.

A 71-year-old black woman was admitted to the hospital with a 2-month history of a nonhealing leg ulcer. Her medical history included diabetes mellitus type 2, congestive heart failure, allergic rhinitis, and asthma. The patient's asthma was labile and steroid-dependent until 2 years before admission, at which time zafirlukast therapy was started. On further questioning, the patient revealed a 6-month history of malaise and a 40-lb weight loss. A physical examination showed a 2-cm Stage 3 ulcer on the medial aspect of the right ankle with diminished sensation in both feet and left footdrop. Electromyography revealed mononeuritis multiplex. The patient's white blood cell count was 11,100/mm3 with 60% eosinophils. A sural nerve biopsy showed vasculitis consistent with Churg-Strauss syndrome. One week after prednisone therapy was initiated, the patient's foot strength was nearly normal and her eosinophilia had resolved. Although Churg-Strauss syndrome is a rare disorder, in the setting of asthma and multiple disparate signs and symptoms, the broad diagnostic category of serious vasculitic illness should be considered.

Nerve and ganglion blood flow in diabetes: an appraisal.

Vasa nervorum, the vascular supply to peripheral nerve trunks, and their associated cell bodies in ganglia have unique anatomical and physiological characteristics. Several different experimental approaches toward understanding the changes in vase nervorum following injury and disease have been used. Quantative techniques most widely employed have been microelectrode hydrogen clearance palarography and [14C]iodoantipyrine autoradiographic distribution, whereas estimates of red blood cell flux using a fiber-optic laser Doppler probe offer real time data at different sites along the nerve trunk. There are important caveats about the use of these techniques, their advantages, and their limitations. Reports of nerve blood flow require careful documentation of physiological variables, including mean arterial pressure and nerve temperature during the recordings. Several ischemic models of the peripheral nerve trunk have addressed the ischemic threshold below which axonal degeneration ensues (< 5ml/100 g/min). Following injury, rises in local blood flow reflect acitons of vasoactive peptides, nitric oxide, and the development of angiogenesis. In experimental diabetes, a large number of studies have documented reductions in nerve blood flow and tandem corrections of nerve blood flow and conduction slowing. A significant proportions, however, of the work can be criticized on the basis of methodology and interpretation. Similarly, not all work has confirmed that reductions of nerve blood flow are an invariable feature of experimental or human diabetic polyneuropathy. Therefore, while there is disagreement as to whether early declines in nerve blood flow "account" for diabetic polyneuropathy, there is unquestioned eveidence of early microangiopathy. Abnormalities of vase nervorum and micorvessels supplying ganglia at the very least develop parallel to and together with changes in neurons, Schwann cells, and axons.

Quantitative assessment of the innervation of epineurial arteries in the peripheral nerve by immunofluorescence: differences between controls and patients with peripheral arterial disease.

The peripheral nerve is supplied by the vasa nervorum. The epi- and perineurial vessels are innervated by an autonomic plexus, which plays a role in regulation of the endoneurial blood flow. This innervation is decreased in diabetes and alcohol polyneuropathy and seems to precede the development of diabetic polyneuropathy. A decreased innervation may therefore play a role in the development of polyneuropathy. In peripheral arterial disease (PAD) clinical and morphological features are present, related to severity of ischemia. To investigate the innervation of the vasa nervorum in severe ischemia, we performed immunofluorescence staining with the general neural marker protein gene product (PGP) 9.5 in whole mount preparations of epineurial vessels of nine sural nerves taken from patients with legs amputated because of severe PAD (59+/-15 years, mean +/- SD) and ten age-matched controls (61+/-24 years). In patients with PAD the nerve density of the perivascular plexus was decreased in comparison with controls (mean intercept density/mm +/- SD) 26.0+/-6.9 in PAD and 39.9+/-10.7 in controls, area% 6.0+/-1.6 in PAD and 9.9+/-2.6 in controls, both P<0.01, t-test). A decreased perivascular plexus may result in a diminished regulation of the endoneurial blood flow in patients with severe PAD.

Do denervated peripheral nerve trunks become ischemic? The impact of chronic denervation on vasa nervorum.

The long-term relationship between the peripheral nerve trunk and its vascular supply, the vasa nervorum, has not been considered in the context of denervation and regeneration. While the microvessels of peripheral nerve are not thought to influence Wallerian degeneration itself, in this work we explored how vasa nervorum respond to denervation of the nerve trunk. Our hypotheses were that the presence of axons had a significant impact on the vasa nervorum and that the absence of reinnervation might eventually lead to an unfavorable ischemic regenerative microenvironment. We studied rat sciatic nerve trunks for up to 6 months following transection and either prevented regeneration or allowed it to proceed. Vasa nervorum were studied in several ways: (i) measurements of local endoneurial blood flow using microelectrode hydrogen clearance polarography; (ii) measurements of erythrocyte flux (flow) in the extrinsic nerve plexus using laser Doppler flowmetry; (iii) India ink perfusion of microvessels in unfixed nerve; (iv) mRNA expression of vascular endothelial growth factor (VEGF) using reverse transcription polymerase chain reaction. Early after injury, there were rises in endoneurial and extrinsic flow, microvessel numbers, and VEGF mRNA expression. Angiogenesis was apparently confined to the epineurial and perineurial compartments. Later, however, there were substantial declines in flow observed in long-term (6-month) denervated sciatic nerve trunks associated with declines in the caliber of new microvessels. Reinnervated sciatic nerves had restored endoneurial blood flow. The findings confirm important relationships between axon presence and local blood flow. Angiogenesis is a feature of the injured peripheral nerve, but long term denervated nerve trunks have declines of flow despite retaining new microvessels.

Horner's syndrome after carotid endarterectomy--a case report.

Horner's syndrome is described in a patient with anisocoria and unilateral lid ptosis 48 hours after an ipsilateral carotid endarterectomy. This case illustrates a rare iatrogenic complication of sympathetic nerve dysfunction following elective surgery.

Reversal of experimental diabetic neuropathy by VEGF gene transfer.

The pathogenetic basis for diabetic neuropathy has been enigmatic. Using two different animal models of diabetes, we have investigated the hypothesis that experimental diabetic neuropathy results from destruction of the vasa nervorum and can be reversed by administration of an angiogenic growth factor. Nerve blood flow, as measured by laser Doppler imaging or direct detection of a locally administered fluorescent lectin analogue, was markedly attenuated in rats with streptozotocin-induced diabetes, consistent with a profound reduction in the number of vessels observed. A severe peripheral neuropathy developed in parallel, characterized by significant slowing of motor and sensory nerve conduction velocities, compared with nondiabetic control animals. In contrast, 4 weeks after intramuscular gene transfer of plasmid DNA encoding VEGF-1 or VEGF-2, vascularity and blood flow in the nerves of treated animals were similar to those of nondiabetic control rats; constitutive overexpression of both transgenes resulted in restoration of large and small fiber peripheral nerve function. Similar experiments performed in a rabbit model of alloxan-induced diabetes produced comparable results. These findings support the notion that diabetic neuropathy results from microvascular ischemia involving the vasa nervorum and suggest the feasibility of a novel treatment strategy for patients in whom peripheral neuropathy constitutes a secondary complication of diabetes.

Polyneuropathy in late Lyme borreliosis - a clinical, neurophysiological and morphological description.

In a prospective study, detailed clinical and neurophysiological examinations were performed in 17 patients with polyneuropathy associated with the late borrelial manifestation acrodermatitis chronica atrophicans (ACA). Similar clinical and neurophysiological signs were found in most of the patients. The findings were those of a sensory polyneuropathy, mainly affecting large nerve fibres. Marked abnormality of vibration threshold was a common finding and in 4 patients this raised a suspicion of spinal cord engagement, in addition to a polyneuropathy. Sural nerve biopsy, performed in 3 of the patients, showed a mainly axonal neuropathy. Biopsy findings did not confirm earlier reports of vasculitis of epineural vessels in ACA-associated polyneuropathy.

Identification of the characteristic vascular changes in a sural nerve biopsy of a case with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy' (CADASIL) has recently been identified as a hereditary disorder with characteristic fine structural changes of small intracerebral arteries and arterioles. Electron microscopically there are characteristic perivascular deposits of granular electron-dense material resembling immunoglobulin deposits. The present case from a family with four affected members in three successive generations shows that similar vascular changes as described in the central nervous system are present in blood vessels of the sural nerve, although less pronounced and, therefore, affording electron microscopy for their unequivocal detection. Nevertheless it has been shown for the first time that the diagnosis of CADASIL can be verified by a sural nerve biopsy. Occasional focal accumulation of pinocytotic vesicles opposite the granular deposits suggests exocytosis as one of the possible pathomechanisms for their production.