[Show abstract][Hide abstract] ABSTRACT: Introduction:
A 24-year-old man with primary hyperoxaluria type 1 (PH1) presented with a rapidly progressive axonal and demyelinating sensorimotor polyradiculoneuropathy shortly after the onset of end-stage renal disease. His plasma oxalate level was markedly elevated at 107 µmol/L (normal<1.8 µmol/L).
A sural nerve biopsy was performed. Teased fiber and paraffin and epoxy sections were done and morphometric procedures were performed on this sample and on an archived sample from a 22-year-old man as an age- and gender-matched control. Embedded teased fiber electron microscopy was also performed.
The biopsy revealed secondary demyelination and axonal degeneration. Under polarized light, multiple bright hexagonal, rectangular, and starburst inclusions, typical of calcium oxalate monohydrate crystals, were seen.
The proposed mechanisms of nerve damage include disruption of axonal transport due to crystal deposition, toxic effect of oxalate, or nerve ischemia related to vessel occlusion from oxalate crystal deposition.
[Show abstract][Hide abstract] ABSTRACT: To understand the pathologic and clinical correlates of patients with chronic meralgia paresthetica (MP) undergoing lateral femoral cutaneous nerve (LFCN) neurectomy.
A retrospective cohort approach was utilized to identify 7 patients undergoing LFCN neurectomy for intractable pain. Control autopsied LFCN was obtained. Clinical, radiologic, and electrophysiologic features were reviewed.
In identified cases, preoperative symptoms included severe lateral thigh pain and numbness. The duration of symptoms prior to surgery ranged from 2 to 15 years. Body mass index (BMI) varied from 20 kg/m(2) to 44.8 kg/m(2) (normal-morbidly obese), with 6 out of 7 patients being obese. No patients were diabetic. Focal nerve indentation at the inguinal ligament was seen intraoperatively and on gross pathology in 4 of 7 cases. Multifocal fiber loss, selective loss of large myelinated fibers, thinly myelinated profiles, regenerating nerve clusters, perineurial thickening, and subperineurial edema were seen. None of these features were observed in control nerve. Morphometric analysis confirmed loss of large myelinated fibers with small and intermediate size fiber predominance. Five patients had varying degrees of intraneural and epineurial inflammation. Six of 7 reported improved pain after neurectomy, sometimes dramatic.
Patients with chronic MP and intractable pain have an LFCN mononeuropathy with loss of nerve fibers. Pathologic and clinical study supports a compressive pathogenesis as the primary mechanism. Abnormal nerve inflammation coexists and may play a role in pathogenesis. These selected patients typically benefited from neurectomy at a site of inguinal ligament compression.
This study provides Class IV evidence that patients with chronic MP LFCN neurectomy experience improvement in MP-related pain.
[Show abstract][Hide abstract] ABSTRACT: To study the clinical, electrophysiological and pathological characteristics and outcome of immune-mediated neuropathy (IMN) following stem cell transplantation (SCT).
Retrospective chart review of the Mayo Clinic Rochester SCT database between January 1997 and August 2012.
Of the 3305 patients who underwent SCT, 12 patients (0.36%) had IMN. The median time from SCT to IMN was 7 months. IMN typically presented as an asymmetric radiculoplexus neuropathy (7/12 patients) or acute polyradiculoneuropathy (Guillain-Barré syndrome) (4/12). Neurophysiology showed demyelinating neuropathy in four patients and axonal neuropathy in eight. Cerebrospinal fluid protein was increased in five of six patients (median 67 mg/dL). The Neuropathy Impairment Score (NIS) improved in all patients (mean NIS 43-10, p=0.016). Six patients died. One patient died from complications of IMN and one died from complications of the haematological disease. Five patients had recurrence of their malignancy within 4 months of the IMN and of these, four died.
IMN occurs rarely in patients after SCT. Two possible mechanisms include (1) an immune reconstitution syndrome, supported by stereotypical neuropathy types (radiculoplexus and polyradiculoneuropathies), monophasic course and temporal association with SCT and (2) a paraneoplastic phenomenon, supported by frequent early malignancy recurrence following IMN.
Journal of neurology, neurosurgery, and psychiatry 11/2013; 85(6). DOI:10.1136/jnnp-2013-306657 · 6.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives:
Our first objective was to explore the value of estimating 95% confidence intervals (CIs) of epidermal nerve fibers (ENFs)/mm for number of sections to be evaluated and for confidently judging normality or abnormality. Our second objective was to introduce a new continuous measure combining nerve conduction and ENFs/mm.
The 95% CI studies were performed on 1, 1-2, 1-3 - - - 1-10 serial skip sections of 3-mm punch biopsies of leg and thigh of 67 healthy subjects and 23 patients with diabetes mellitus.
Variability of differences of ENFs/mm counts (and 95% CIs) from evaluation of 1, 1-2, 1-3 - - - 1-9 compared with 1-10 serial skip sections decreased progressively without a break point with increasing numbers of sections evaluated. Estimating 95% CIs as sections are evaluated can be used to judge how many sections are needed for adequate evaluation, i.e., only a few when counts and 95% CIs are well within the range of normality or abnormality and more when values are borderline. Also provided is a methodology to combine results of nerve conduction and ENFs/mm as continuous measures of normality or abnormality.
Estimating 95% CIs of ENFs/mm is useful to judge how many sections should be evaluated to confidently declare counts to be normal or abnormal. Also introduced is a continuous measure of both large-fiber (nerve conduction) and small-fiber (ENFs/mm) normal structures/functions spanning the range of normality and abnormality for use in therapeutic trials.
[Show abstract][Hide abstract] ABSTRACT: We present the case of a 67-year-old man with a malignant peripheral nerve sheath tumor (MPNST) affecting the brachial plexus. He presented with progressive right upper extremity paresthesias, numbness, weakness, and severe pain. Nerve conduction studies/electromyography demonstrated a right lower and middle trunk predominant brachial plexopathy. Three-tesla magnetic resonance imaging of the brachial plexus showed a soft tissue mass with central necrosis and cystic changes and irregular contrast enhancement. Positron emission tomography showed increased fluorodeoxyglucose uptake within the mass. Targeted fascicular nerve biopsy revealed hypercellular tumor, featuring atypical cells with mitotic figures and limited immunoreactivity for S-100 protein. The findings were those of an MPNST. The effects on the variably involved fascicles were also seen in teased fiber preparations, paraffin sections, and through immunohistochemistry. This case illustrates the presentation of this rare type of tumor, and characteristic neuroimaging and pathologic features of MPNSTs.
Journal of clinical neuromuscular disease 09/2012; 14(1):28-33. DOI:10.1097/CND.0b013e318260b396
[Show abstract][Hide abstract] ABSTRACT: Occasionally, diabetic patients develop painless, lower-limb, motor predominant neuropathy. Whether this is a variant of diabetic lumbosacral radiculoplexus neuropathy (DLRPN) (a painful disorder from ischemic injury and microvasculitis), a variant of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) or another disorder is unsettled. Here, we characterize the clinical and pathological features of painless diabetic motor predominant neuropathy.
We identified patients with this syndrome who underwent nerve biopsy. We compared pathological features to 33 DLRPN and 25 CIDP biopsies.
23 patients were identified (22 had type 2 diabetes mellitus); 12 men; median age 62.2 years (range 36-78); median weight loss 30 pounds (range 0-100). Overall, the clinical features were similar to DLRPN except painless patients had more symmetrical and upper limb involvement, with slower progression and more severe impairment. Physiological testing demonstrated pan-modality sensory loss, autonomic abnormalities and axonal polyradiculoneuropathies. Nerve biopsies were similar to DLPRN showing ischemic injury (multifocal fiber loss [11/23], perineural thickening [18/23], injury neuroma [11/23], neovascularization [17/23]) and evidence of altered immunity and microvasculitis (epineurial perivascular inflammation [23/23], prior bleeding [11/23], vessel wall inflammation [15/23], and microvasculitis [3/23]). In contrast, CIDP biopsies did not show ischemic injury or microvasculitis but revealed demyelination and onion-bulbs.
1) Painless diabetic motor neuropathy is painless DLRPN and not CIDP and is caused by ischemic injury and microvasculitis. 2) The clinical features of painless DLRPN are different from typical DLPRN being more insidious and symmetrical with slower evolution. 3) The slower evolution may explain the lack of pain.
Annals of Neurology 06/2011; 69(6):1043-54. DOI:10.1002/ana.22334 · 9.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report a patient who developed subacute facial-predominant numbness and anhidrosis, oral incoordination, and esophageal achalasia with resultant cachexia. Great auricular nerve biopsy showed extensive epineurial perivascular inflammatory infiltrates. Sensation, sweating, and swallowing improved with pulse intravenous methylprednisolone given over 5 years. We suggest that the patient's deficits, including achalasia, were due to an immune-mediated sensory and autonomic neuropathy and that, in such cases, pathologic studies of the great auricular nerve may be diagnostically informative.
[Show abstract][Hide abstract] ABSTRACT: Post-surgical neuropathies are usually attributed to mechanical factors, such as compression, stretch, contusion or transection. The role of inflammatory mechanisms in neuropathies occurring after surgeries is poorly appreciated and not well characterized, and may provide a rationale for immunotherapy. A total of 23 selected patients with post-surgical neuropathies received nerve biopsies, of which 21 demonstrated increased inflammation. Here we report the clinical features in these 21 cases of biopsy-confirmed and 12 cases of clinically suspected post-surgical inflammatory neuropathies, in whom no trauma to the nerves was documented. All neuropathies developed within 30 days of a surgical procedure. Of 33 patients, 20 were male and the median age was 65 years (range 24-83). Surgical procedures were orthopaedic (n=14), abdominal/pelvic (n=12), thoracic (n=5) and dental (n=2). Patients developed focal (n=12), multifocal (n=14) or diffuse (n=7) neuropathies. Focal and multifocal neuropathies typically presented with acute pain and weakness, and focal neuropathies often mimicked mechanical aetiologies. Detailed analyses, including clinical characteristics, electrophysiology, imaging and peripheral nerve pathology, were performed. Electrophysiology showed axonal damage. Magnetic resonance imaging of roots, plexuses and peripheral nerves was performed in 22 patients, and all patients had abnormally increased T(2) nerve signal, with 20 exhibiting mild (n=7), moderate (n=12) or severe (n=1) enlargement. A total of 21 patients had abnormal nerve biopsies that showed increased epineurial perivascular lymphocytic inflammation (nine small, five moderate and seven large), with 15 diagnostic or suggestive of microvasculitis. Evidence of ischaemic nerve injury was seen in 19 biopsies. Seventeen biopsies had increased axonal degeneration suggesting active neuropathy. Seventeen biopsied patients were treated with immunotherapy. In 13 cases with longitudinal follow-up (median 9 months, range 3-71 months), the median neuropathy impairment score improved from 30 to 24 at the time of last evaluation (P=0.001). In conclusion: (i) not all post-surgical neuropathies are mechanical, and inflammatory mechanisms can be causative, presenting as pain and weakness in a focal, multifocal or diffuse pattern; (ii) these inflammatory neuropathies may be recognized by their spatio-temporal separation from the site and time of surgery and by the characteristic magnetic resonance imaging features; (iii) occasionally post-surgical inflammatory and mechanical neuropathies are difficult to distinguish and nerve biopsy may be required to demonstrate an inflammatory mechanism, which in our cohort often, but not exclusively, exhibited pathological features of microvasculitis and ischaemia; and (iv) recognizing the role of inflammation in these patients' neuropathy led to rational immunotherapy, which may have resulted in the subsequent improvement of neurological symptoms and impairments.
[Show abstract][Hide abstract] ABSTRACT: We sought to determine the clinical, electrophysiological, neuroimaging, and pathological features of inflammatory pseudotumor of nerve. Five patients were identified. All cases presented with a gradually progressive mononeuropathy with symptoms of weakness, sensory loss, and prominent neuropathic pain. The median duration of symptoms was 7 months (range 3-36 months). Electrophysiological results were in keeping with chronic axonal mononeuropathies with variable findings of active denervation and reinnervation. MRI demonstrated irregular, large masses involving and surrounding nerve with heterogenous signal characteristics on T1- and T2-weighted and post-contrast sequences. Histopathological features of the nerve slightly varied but shared commonalities including chronic inflammatory infiltrates, increased collagen, and increased numbers of microvessels. Axonal degeneration and decreased density of myelinated fibers were also noted. Three patients were treated with weekly courses of intravenous steroids for 3 months. All reported improvement in pain and weakness. Inflammatory pseudotumor of nerve is not a neoplasm and has reactive features of inflammation, increased vascularity, and marked fibrosis. It presents as a progressive axonal mononeuropathy with weakness, sensory loss, and pain that may be episodic. The primary pathophysiology is unknown but the inflammation and response to treatment suggests that there may be an immune component.
Journal of the Peripheral Nervous System 09/2010; 15(3):216-26. DOI:10.1111/j.1529-8027.2010.00273.x · 2.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We present a case of a 60-year-old man with mild type 2 diabetes mellitus and step-wise progression of bilateral lower limb weakness, numbness, and pain over a 1-year period. At the time of evaluation, he used a walker. He had elevated cerebrospinal fluid protein, abnormal cooling and heat-pain thresholds on quantitative sensory testing, and nerve conduction studies/electromyography consistent with bilateral lumbosacral radiculoplexus neuropathies. Because it was not clear whether the disease was still active, a right superficial peroneal nerve biopsy was performed and showed evidence of active axonal degeneration, ischemic injury, and microvasculitis. On the basis of these results, the patient was diagnosed with diabetic lumbosacral radiculoplexus neuropathy and was treated with weekly intravenous methylprednisolone with marked improvement of neurologic symptoms and signs. This case illustrates the typical clinical, electrophysiologic, and pathologic features of diabetic lumbosacral radiculoplexus neuropathy and the utility of nerve biopsy to judge ongoing disease activity.
Journal of clinical neuromuscular disease 10/2009; 11(1):44-8. DOI:10.1097/CND.0b013e3181b1eb6d
[Show abstract][Hide abstract] ABSTRACT: The natural history of intraneural perineurioma has been inadequately studied. The aim of this study was to characterize the clinical presentation, electrophysiologic and imaging features and outcome of intraneural perineurioma. We ask if intraneural perineurioma is a pure motor syndrome that remains confined to one nerve and should be treated by surgical resection. We examined the nerve biopsies of cases labelled perineurioma and selected those with diagnostic features. Thirty-two patients were identified; 16 children and 16 adults; 16 males and 16 females. Median age of onset of neurological symptoms was 14 years (range 0.5-55 years) and median age at evaluation was 17 years (range 2-56 years). All patients had motor deficits; however, mild sensory symptoms or signs were experienced by 27 patients; 'prickling' or 'asleep numbness' in 20, mild pain in 13 and sensory loss in 23. The sciatic nerve or its branches was most commonly affected in 15, followed by brachial plexus, radial nerve and ulnar nerve (four each). Magnetic resonance imaging demonstrated nerve enlargement (29/32), T1 isointensity (27/32), T2 hyperintensity (25/32) and contrast enhancement (20/20). Diagnoses were made based on targeted biopsy of the focal nerve enlargement identified by imaging. Neurological impairment was of a moderate severity (median Neuropathy Impairment Score was 12 points, range 2-49 points). All patients had focal involvement with 27 involving one nerve and five involving a plexus (one bilateral). Long-term follow-up was possible by telephone interview for 23 patients (median 36 months, range 2-177 months). Twelve patients also had follow-up neurologic evaluation (median 45 months, range 10-247 months). The median Neuropathy Impairment Score had changed from 12.6 to 15.4 points (P = 0.19). In all cases, the distribution of neurologic findings remained unchanged. Median Dyck Disability Score was 3 (range 2-5) indicating a mild impairment without interfering with activities of daily living. Ten patients judged their symptoms unchanged, nine slightly worse and four slightly better. We conclude intraneural perineurioma is a benign hypertrophic (non onion bulb) peripheral nerve tumour that presents insidiously in young people and is motor predominant with mild sensory involvement. It is most often a mononeuropathy, but a plexopathy can occur. Diagnosis of this condition requires clinical suspicion, imaging, targeted fascicular biopsy of the lesion and expertise of nerve pathologists. As these tumours are static or slowly progressive, remain confined to their original distribution and have low morbidity, they probably should not be resected routinely. Because intensive evaluation is needed for diagnosis, intraneural perineurioma is probably under-recognized.
[Show abstract][Hide abstract] ABSTRACT: Misdirection of regenerating axons is one of the factors that can explain the poor results often found after nerve injury and repair. In this study, we quantified the degree of misdirection and the effect on recovery of function after different types of nerve injury and repair in the rat sciatic nerve model; crush injury, direct coaptation, and autograft repair. Sequential tracing with retrograde labeling of the peroneal nerve before and 8 weeks after nerve injury and repair was performed to quantify the accuracy of motor axon regeneration. Digital video analysis of ankle motion was used to investigate the recovery of function. In addition, serial compound action potential recordings and nerve and muscle morphometry were performed. In our study, accuracy of motor axon regeneration was found to be limited; only 71% (+/-4.9%) of the peroneal motoneurons were correctly directed 2 months after sciatic crush injury, 42% (+/-4.2%) after direct coaptation, and 25% (+/-6.6%) after autograft repair. Recovery of ankle motion was incomplete after all types of nerve injury and repair and demonstrated a disturbed balance of ankle plantar and dorsiflexion. The number of motoneurons from which axons had regenerated was not significantly different from normal. The number of myelinated axons was significantly increased distal to the site of injury. Misdirection of regenerating motor axons is a major factor in the poor recovery of nerves that innervate different muscles. The results of this study can be used as basis for developing new nerve repair techniques that may improve the accuracy of regeneration.
[Show abstract][Hide abstract] ABSTRACT: Nerve microvasculitis and ischemic injury appear to be the primary and important pathogenic alterations in lumbosacral radiculoplexus neuropathy of patients with (DLRPN) and without (LRPN) diabetes mellitus (DM). Here, we examine the involvement of inflammatory mediators in DLRPN and LRPN. Paraffin sections of sural nerves from 19 patients with DLRPN, 13 patients with LRPN, and 20 disease control patients were immunostained for intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and nuclear factor kappaB (NF-kappaB). The findings were correlated with histopathology. The pathologic and immunohistochemical alterations of DLRPN and LRPN nerves were indistinguishable. The nerves of both types of LRPN had a significantly greater number of ICAM-1 positive vessels than did the controls (P < 0.01). TNF-alpha expression was seen in Schwann cells and some macrophages of DLRPN and LRPN nerves, whereas IL-6 expression was minimal. There was greater NF-kappaB immunoreactivity in vessels and endoneurial cells of DLRPN and LRPN nerves than of the controls (P < 0.001). NF-kappaB expression correlated with the number of empty nerve strands (P < 0.01) and the frequency of axonal degeneration (P < 0.05), whereas TNF-alpha expression correlated inversely with the number of empty nerve strands of teased fibers (P < 0.05). Our findings suggest that up-regulation of inflammatory mediators target different cells at different disease stages and that these mediators may be sequentially involved in an immune-mediated inflammatory process that is shared by both DLRPN and LRPN. Up-regulated inflammatory mediators may be immunotherapeutic targets in these two conditions.