Sural nerve biopsy utility by masked assessment of individual histologic preparations.

BACKGROUND AND AIMS: Comprehensive study of sural nerve biopsy utility based on individual histopathologic preparations is lacking. We aimed to quantify the value of different histologic preparations in diagnosis. METHODS: One hundred consecutive sural nerves were studied by standard histological preparations plus graded teased nerve fibers (GTNF), immunohistochemistry, and epoxy-semithin morphometry. Three examiners scored the individual preparations separately by a questionnaire of neuropathic and interstitial abnormalities, masked to the biopsy number, versus a gold-standard of all preparations. Multivariate modeling was utilized to determine best approach versus the gold-standard. RESULTS: Highest confidence (range 8-9 of 10) and inter-rater reliability (99%) for fiber abnormalities came from GTNF, and interstitial abnormalities from paraffin stains (range 7-8, 99%). Vasculitic neuropathy associated with GTNF axonal degeneration (moderate to severe 79%) with OR 3.8, 95% CI (1.001-14.7), p = .04, but not significantly with the other preparations. Clinicopathologic diagnoses associated with teased fiber abnormalities in chronic inflammatory demyelinating polyradiculoneuropathy, 80% (8/10); amyloidosis, 50% (1/2); adult-onset polyglucosan disease 100% (1/1). GTNF and paraffin stains significantly correlated with fiber density determined by morphometric analysis (GTNF: OR 9.9, p < .0001, paraffin: OR 3.8, p = .03). GTNF combined with paraffin sections had highest accuracy for clinicopathologic diagnoses and fiber density with 0.86 C-stat prediction versus morphometric analysis. Pathological results lead to initiation or changes of immunotherapy in 70% (35/50; initiation n = 22, reduction n = 9, escalation n = 4) with the remaining having alternative intervention or no change. INTERPRETATION: Nerve biopsy paraffin stains combined with GTNF have highest diagnostic utility, confidence, inter-rater reliability, improving accuracy for a pathologic diagnosis aiding treatment recommendations. Immunostains and epoxy preparations are also demonstrated useful supporting consensus guidelines. This study provides class II evidence for individual nerve preparation utility.

Novel imaging techniques using 18 F-florbetapir PET/MRI can guide fascicular nerve biopsy in amyloid multiple mononeuropathy.

BACKGROUND: Multiple mononeuropathy is a rare presentation of primary (AL) amyloidosis and nerve biopsy is usually needed for diagnosis. Conventional imaging is useful to identify proximal nerve involvement but may be inadequate. We report a patient with multiple mononeuropathy whose presentation was suggestive of AL amyloid neuropathy and in whom repeated tissue biopsies were negative for amyloid (including two sensory nerves and one muscle). METHODS: The patient underwent magnetic resonance imaging (MRI) and whole body 18 F-florbetapir positron emission tomography (PET)/MRI. RESULTS: Whole body 18 F-florbetapir PET/MRI revealed abnormal low-level florbetapir uptake in the right proximal tibial and peroneal nerves, which provided a target for a sciatic bifurcation fascicular nerve biopsy that was diagnostic of AL amyloidosis. CONCLUSIONS: 18 F-florbetapir PET/MRI imaging is a promising diagnostic tool for patients with suspected peripheral nerve amyloidosis (including multiple mononeuropathy) in whom conventional imaging and nerve and muscle biopsies miss the pathology.

Expanded teased nerve fibre pathological conditions in disease association.

OBJECTIVE: To describe an expanded teased nerve fibre classification in disease association. METHODS: We reviewed four newly proposed teased nerve fibre types (Types J-M): Type J, rope-like fibres; K, fibril-like clumps of osmium positivity; L, cellular debris along and within nerve fibres; M, circular axonal inclusions surrounded by thin myelin. Different clinical pathological entities were studied for these fibre types including chronic inflammatory demyelinating polyradiculoneuropathy (CIDP: N=20); amyloid polyneuropathy (N=20); intraneural B-cell lymphoma (N=20) or adult-onset polyglucosan body disease (APBD: N=6) in comparison with 112 disease controls. Student's t-test was used to test significance of association between the identified fibre types and the specific clinical diagnosis. RESULTS: Each fibre type significantly associated (p<0.001) with particular disease categories: Type J, 60% of CIDP cases; Type K, 75% of amyloid cases; Type L, 75% of intraneural lymphoma cases; Type M, 100% of APBD cases. Rarely were these fibres found in the other disease control cases ≤3% of cases. In three cases, the teased fibre findings were so striking additional paraffin nerve preparations were made to make the pathological diagnosis when initial paraffin sections were non-diagnostic. CONCLUSIONS: Teased nerve fibre Types J-M associate with commonly seen pathological diagnosis and are helpful in the consideration of specific neuropathy diagnoses.

Onion-bulb patterns predict acquired or inherited demyelinating polyneuropathy.

INTRODUCTION: Onion-bulbs (OB) are concentrically layered Schwann-cell processes, surrounding nerve fibers, occurring in both inherited and acquired demyelinating polyneuropathies. We investigated whether OB patterns (generalized, mixed, or focal) correlate with acquired or inherited neuropathies. METHODS: One hundred thirty-one OB-rich nerve biopsies were graded for OB pattern and inflammation without knowledge of clinical history. We classified inherited (n = 49) or acquired (n = 82) neuropathies based solely on clinical history. RESULTS: Fifty-one biopsies had generalized (34 inherited vs. 17 acquired, P < 0.001), 54 mixed (48 acquired vs. 6 inherited, P < 0.001), and 26 focal/multifocal (inherited [n = 9], acquired [n = 17]) OB. Inflammation occurred more frequently in acquired (n = 54) than inherited (n = 14) neuropathy (P = 0.004). DISCUSSION: Generalized OB correlates with inherited neuropathy; mixed OB with acquired. Inflammation occurs more in acquired neuropathy cases. OB patterns are best explained by ubiquitous Schwann-cell involvement in inherited and multifocal Schwann-cell involvement in acquired neuropathies and predict the electrophysiology of uniform demyelination in inherited and unequal demyelination in acquired neuropathies. Muscle Nerve 59:665-670, 2019.

Somatotopic heat pain thresholds and intraepidermal nerve fibers in health.

INTRODUCTION: For sequential and somatotopic assessment of small fiber neuropathy, heat pain (HP) tests of hypoalgesia might be used instead of decreased counts of epidermal nerve fibers (ENFs), but then healthy subject reference values of HP thresholds are needed. METHODS: Using the Computer Assisted Sensation Evaluator IVc system, HP thresholds of hypoalgesia were estimated for 10 unilateral sites and counts of ENFs for 4 of them in healthy subjects. RESULTS: In healthy subjects, small but statistically significant differences of both HP thresholds of hypoalgesia and counts of ENFs were observed among tested sites. Significant correlations between HP thresholds and counts of ENFs were not found. DISCUSSION: For the studied somatotopic sites, we provide ≥95th and ≥99th percentile reference limits for HP 0.5 and 5 of 1-10 HP thresholds of hypoalgesia and decreased counts of ENFs at ≤5th and ≤1st percentile levels. Muscle Nerve 58: 509-516, 2018.

Clinical-pathologic correlations in voltage-gated Kv1 potassium channel complex-subtyped autoimmune painful polyneuropathy.

INTRODUCTION: Voltage-gated Kv1 potassium channel complex (VGKC) autoantibodies subtyped for leucine-rich glioma-inactivated 1 (LGI1), contactin-associated-proteinlike 2 (CASPR2), and Kv IgGs have a spectrum of neurological presentations. Painful polyneuropathy is seen in some patients, but nerve pathology descriptions are lacking. METHODS: Clinicopathologic features were studied in subtyped VGKC-autoantibody-seropositive patients who had undergone nerve biopsies. RESULTS: Five patients were identified, 1 LGI1 IgG positive and 1 CASPR2 IgG positive, but all negative for Kv1.1-, 1.2-, 1.6-subtyped IgG autoantibodies. Median symptom duration was 17 months. Pain was the predominant symptom; 3 had mild sensory loss and/or weakness. Histopathological abnormalities were limited to axonal loss in 3. None had mononuclear cellular infiltrates. Electron micrographs revealed no interstitial abnormalities. Three patients reported marked improvement in pain with immunotherapy. CONCLUSIONS: The nerve biopsy histopathology of patients subtyped for LGI1 and CASPR2 IgGs within the VGKC-complex spectrum disorders shows either normal density or axonal fiber loss without inflammatory infiltrates. A reversible neural hyperexcitable mechanism is considered to be the cause of this painful polyneuropathy. Muscle Nerve 55: 520-525, 2017.

Immunotherapy-responsive allodynia due to distal acquired demyelinating symmetric (DADS) neuropathy.

INTRODUCTION: Distal acquired demyelinating symmetric (DADS) neuropathy is a distal variant of chronic inflammatory demyelinating polyradiculoneuropathy. It is characterized by chronic distal symmetric sensory or sensorimotor deficits. Sensory ataxia is a common clinical presentation. Nerve conduction studies typically show markedly prolonged distal motor latencies. METHODS: We report 2 patients with chronic progressive generalized pain and fatigue, with normal neurological examinations except for allodynia. RESULTS: Nerve conduction studies were typical of DADS neuropathy. Monoclonal protein studies were negative. Cerebrospinal fluid protein levels were elevated. Sural nerve biopsies revealed segmental demyelination and remyelination. One biopsy had marked endoneurial and epineurial lymphocytic infiltration. Immunomodulatory therapy alleviated the pain and fatigue and markedly improved distal motor latencies in both patients. CONCLUSIONS: DADS neuropathy can present with pain and a normal neurological examination apart from allodynia. Nerve conduction studies are necessary for diagnosis. These patients respond to immunotherapy better than typical DADS neuropathy patients with sensory ataxia. Muscle Nerve 54: 973-977, 2016.

Progressive polyradiculoneuropathy due to intraneural oxalate deposition in type 1 primary hyperoxaluria.

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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Immune-mediated neuropathies following stem cell transplantation.

OBJECTIVE: To study the clinical, electrophysiological and pathological characteristics and outcome of immune-mediated neuropathy (IMN) following stem cell transplantation (SCT). METHODS: Retrospective chart review of the Mayo Clinic Rochester SCT database between January 1997 and August 2012. RESULTS: 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. CONCLUSIONS: 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.

Lumbosacral Radiculoplexus Neuropathy After COVID-19.

INTRODUCTION: Lumbosacral Radiculoplexus Neuropathy (LRPN) is a subacute, painful, paralytic, asymmetric immune-mediated lower-limb neuropathy associated with weight loss and diabetes mellitus (called DLRPN). Approximately one-third of LRPN cases have a trigger. Our purpose is to show that COVID-19 can trigger LRPN. CASE REPORT: We describe the clinical, neurophysiological, radiologic, and pathologic findings of a 55-year-old man who developed DLRPN after severe acute respiratory syndrome coronavirus-2 infection. Shortly after mild coronavirus disease 2019 (COVID-19), the patient developed severe neuropathic pain (allodynia), postural orthostasis, fatigue, weight loss, and weakness of bilateral lower extremities requiring wheelchair assistance. One month after COVID-19, he was diagnosed with type 2 diabetes mellitus. Neurological examination showed bilateral severe proximal and distal lower extremity weakness, absent tendon reflexes, and pan-modality sensation loss. Electrophysiology demonstrated an asymmetric axonal lumbosacral and thoracic radiculoplexus neuropathies. Magnetic resonance imaging showed enlargement and T2 hyperintensity of the lumbosacral plexus. Cerebral spinal fluid (CSF) showed an elevated protein (138 mg/dL). Right sural nerve biopsy was diagnostic of nerve microvasculitis. He was diagnosed with DLRPN and treated with intravenous methylprednisolone 1 g weekly for 12 weeks. The patient had marked improvement in pain, weakness, and lightheadedness and at the 3-month follow-up was walking unassisted. CONCLUSION: COVID-19 can trigger postinfectious inflammatory neuropathies including LRPN.

Amyloid-like IgM deposition neuropathy with multiple mononeuropathies and generalized neuropathy.

Amyloid-like IgM deposition neuropathy is a distinct entity in the setting of IgM monoclonal gammopathy in which endoneurial perivascular entire IgM-particle accumulation leads to a painful sensory followed by motor peripheral neuropathy. We report a 77-year-old man presenting with progressive multiple mononeuropathies starting with painless right foot drop. Electrodiagnostic studies showed severe axonal sensory-motor neuropathy superimposed by multiple mononeuropathies. Laboratory investigations were remarkable for biclonal gammopathy of IgM kappa, IgA lambda and severe sudomotor and mild cardiovagal autonomic dysfunction. A right sural nerve biopsy showed multifocal axonal neuropathy, prominent microvasculitis, and prominent large endoneurial deposits of Congo-red negative amorphous material. Laser dissected mass spectrometry-based proteomics identified IgM kappa deposit without serum amyloid-P protein. This case has several distinctive features, including motor preceding sensory involvement, prominent IgM-kappa proteinaceous deposits replacing most of the endoneurium, a prominent inflammatory component, and improvement of motor strength after immunotherapy.

Painless diabetic motor neuropathy: a variant of diabetic lumbosacral radiculoplexus Neuropathy?

OBJECTIVE: 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. METHODS: We identified patients with this syndrome who underwent nerve biopsy. We compared pathological features to 33 DLRPN and 25 CIDP biopsies. RESULTS: 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. INTERPRETATION: 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.

Nitrofurantoin and Minocycline-Associated Vasculitic Neuropathy: Case Reports and Literature Review.

BACKGROUND: Vasculitic neuropathies usually present acutely to subacutely, with an asymmetric pattern, involving multiple peripheral nerve territories. Drug-induced vasculitis is an often overlooked etiology of vasculitic neuropathy. METHODS: We present the first reported case of nitrofurantoin-associated and an illustrative case of minocycline-associated vasculitic neuropathy, with a review of the literature. RESULTS: The first patient is a 60-year-old woman who developed axonal sensorimotor peripheral neuropathy after nitrofurantoin use, with a superficial radial nerve biopsy confirming vasculitis. The second patient is a 23-year-old woman, with a history of acne vulgaris treated with minocycline, who presented with a subacute right common peroneal mononeuropathy followed by a left deep peroneal mononeuropathy, with elevated antinuclear, perinuclear-antineutrophil cytoplasmic, and myleoperoxidase antibodies, and MPO titers, and a sural nerve biopsy showing large arteriole vasculitis. Finally, we provide a comprehensive review of previously published cases. CONCLUSIONS: Medications should be considered as a trigger for medication-induced vasculitic neuropathy. Accurate diagnosis would ensure timely treatment.

Immune trigeminal sensory neuropathy with esophageal achalasia: improvement with long-term immunotherapy.

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.

Post-surgical inflammatory neuropathy.

UNLABELLED: 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.

Expanding the Spectrum of Chronic Immune Sensory Polyradiculopathy: CISP-Plus.

OBJECTIVE: Sensory loss with normal nerve conduction studies (NCS) from focal sensory root inflammatory demyelination is characteristic of chronic immune sensory polyradiculopathy (CISP). However, nonpure cases involving motor and distal sensory nerves exist (CISP-plus). We hypothesize that CISP-plus and CISP are fundamentally part of the same syndrome through comparison of clinical, neurophysiologic, and pathologic features. METHODS: CISP-plus (primary dorsal root with lesser motor and sensory nerve involvement) and CISP cases were retrospectively analyzed (1986-2019). RESULTS: We identified 44 CISP-plus and 28 CISP cases (n = 72) with 86% (38/44) of patients with CISP-plus and 79% (22/28) of patients with CISP experiencing imbalance. On examination, large fiber sensory loss was present in 98% (43/44) of patients with CISP-plus and 96% (27/28) of patients with CISP. Gait ataxia was evident in 93% (41/44) of patients with CISP-plus and 79% (22/28) of patients with CISP. Mild distal weakness was common in CISP-plus (75%, 33/44). NCS showed mild abnormalities in all patients with CISP-plus and were normal (by definition) in all patients with CISP. Elevated CSF protein, slowing of somatosensory evoked potentials, and MRI root enhancement occurred in most CISP-plus and CISP cases. Eleven CISP-plus nerve biopsies showed loss of large myelinated fibers and onion-bulb formations, most prominent in rootlet biopsies. Immunotherapy resulted in marked improvement of gait ataxia in 84% (27/32) of patients with CISP-plus and 93% (13/14) of patients with CISP with return to normal neurologic examination in half (25/46). CONCLUSION: The recognition of CISP-plus expands the spectrum of CIDP by combining CISP-plus (predominant sensory polyradiculopathy with mild motor and sensory nerve involvement) with pure CISP (focal sensory polyradiculopathy) together as proximal sensory CIDP.

Pure Motor Onset and IgM-Gammopathy Occurrence in Multifocal Acquired Demyelinating Sensory and Motor Neuropathy.

OBJECTIVES: To longitudinally investigate patients with multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy, quantifying timing and location of sensory involvements in motor-onset patients, along with clinico-histopathological and electrophysiological findings to ascertain differences in patients with and without monoclonal gammopathy of uncertain significance (MGUS). METHODS: Patients with MADSAM neuropathy seen at Mayo Clinic and tested for monoclonal gammopathy and ganglioside antibodies, were retrospectively reviewed (January 1st, 2007-December 31st, 2018). RESULTS: Of 76 patients with MADSAM, 53% had pure motor, 16% pure sensory, 30% sensorimotor and 1% cranial nerve onsets. Motor-onset patients were initially diagnosed as multifocal motor neuropathy (MMN). MGUS occurred in 25% (89% IgM subtype), associating with ganglioside autoantibodies (p<0.001) and higher IgM titers (p<0.04). Median time to sensory involvements (confirmed by electrophysiology) in motor-onset patients was 18 months (range: 6-180). Compared to initial motor nerve involvements, subsequent sensory findings were within the same territory 35% (14/40), outside 20% (8/40), or both 45% (18/40). Brachial and lumbosacral plexus MRI was abnormal in 87% (34/39) and 84% (21/25), respectively, identifying hypertrophy and increased T2 signal predominantly in brachial plexus trunks (64%), divisions (69%), and cords (69%), and intrapelvic sciatic (64%) and femoral (44%) nerves. Proximal fascicular nerve biopsies (n=9) more frequently demonstrated onion-bulb pathology (p=0.001) and endoneurial inflammation (p=0.01) than distal biopsies (n=17). MRI and biopsy findings were similar amongst patient subgroups. Initial Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores were higher in patients with MGUS relative to without (p=0.02). Long-term treatment responsiveness by INCAT score reduction ≥1 or motor Neuropathy Impairment Score (mNIS) >8 point reduction occurred in 75% (49/65) irrespective of MGUS or motor-onsets. Most required ongoing immunotherapy (86%). Patients with MGUS more commonly required dual-agent immunotherapy for stability (p=0.02). DISCUSSION: Pure motor-onsets are the most common MADSAM presentation. Long-term follow-up, repeat electrophysiology and nerve pathology help distinguish motor-onset MADSAM from MMN. Better long-term immunotherapy responsiveness occurs in motor-onset MADSAM compared to MMN reports. Patients having MGUS commonly require dual immunotherapy. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that most clinical, electrophysiological, and histopathological findings were similar between patients with MADSAM with and without monoclonal gammopathy of unknown significance.

Inflammatory pseudotumor of nerve: clinicopathological characteristics and a potential therapy.

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.

Longitudinal study of intraneural perineurioma--a benign, focal hypertrophic neuropathy of youth.

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.