Red nucleus IL-33 facilitates the early development of mononeuropathic pain in male rats by inducing TNF-α through activating ERK, p38 MAPK, and JAK2/STAT3.

BACKGROUND: Our recent studies have identified that the red nucleus (RN) dual-directionally modulates the development and maintenance of mononeuropathic pain through secreting proinflammatory and anti-inflammatory cytokines. Here, we further explored the action of red nucleus IL-33 in the early development of mononeuropathic pain. METHODS: In this study, male rats with spared nerve injury (SNI) were used as mononeuropathic pain model. Immunohistochemistry, Western blotting, and behavioral testing were used to assess the expressions, cellular distributions, and actions of red nucleus IL-33 and its related downstream signaling molecules. RESULTS: IL-33 and its receptor ST2 were constitutively expressed in the RN in naive rats. After SNI, both IL-33 and ST2 were upregulated significantly at 3 days and peaked at 1 week post-injury, especially in RN neurons, oligodendrocytes, and microglia. Blockade of red nucleus IL-33 with anti-IL-33 neutralizing antibody attenuated SNI-induced mononeuropathic pain, while intrarubral administration of exogenous IL-33 evoked mechanical hypersensitivity in naive rats. Red nucleus IL-33 generated an algesic effect in the early development of SNI-induced mononeuropathic pain through activating NF-κB, ERK, p38 MAPK, and JAK2/STAT3, suppression of NF-κB, ERK, p38 MAPK, and JAK2/STAT3 with corresponding inhibitors markedly attenuated SNI-induced mononeuropathic pain or IL-33-evoked mechanical hypersensitivity in naive rats. Red nucleus IL-33 contributed to SNI-induced mononeuropathic pain by stimulating TNF-α expression, which could be abolished by administration of inhibitors against ERK, p38 MAPK, and JAK2/STAT3, but not NF-κB. CONCLUSIONS: These results suggest that red nucleus IL-33 facilitates the early development of mononeuropathic pain through activating NF-κB, ERK, p38 MAPK, and JAK2/STAT3. IL-33 mediates algesic effect partly by inducing TNF-α through activating ERK, p38 MAPK and JAK2/STAT3.

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.

[Multiple mononeuropathy associated with systemic sclerosis with vasculitis confirmed by nerve biopsy: a case report].

A 68-year-old woman with a medical history of interstitial pneumonia associated with systemic sclerosis (SSc) presented with numbness of the lower limbs and left drop foot. She was diagnosed with multiple mononeuropathy based on the laterality of her symptoms, muscle weakness, thermal hypoalgesia, and nerve conduction study findings. Left sural nerve biopsy showed vasculitis, and steroid therapy was effective. This case highlights the importance of histopathological assessment to select an appropriate treatment strategy.

Clinicopathological features of multiple mononeuropathy associated with systemic lupus erythematosus: a multicenter study.

Multiple mononeuropathy (MM) occurs rarely during systemic lupus erythematosus (SLE) but may lead to major disability. The aim of this study was to investigate the clinic-pathological presentations of MM during SLE, as well as long-term outcomes. We conducted a multicentric retrospective study that included patients receiving a diagnosis of MM during SLE. Ten patients were included (8 women and 2 men, median age at MM diagnosis: 40.4 years). SLE was diagnosed before MM in 9/10 patients (median time 8.2 years). When MM occurred, the SLEDAI score was ≥6 for 6/9 patients. Presenting symptoms consisted of sensory deficits (n = 10), neuropathic pain (n = 9), and/or motor deficits (n = 9), sometimes symmetrical, affecting the lower limbs (10/10) and occasionally the upper limbs (5/10). All patients presented with uni- or bilateral damage of the common fibular nerve, with less frequent involvement of the tibial nerve. Serum cryoglobulinemia was positive in 5/9 patients. Electrophysiological studies confirmed the non-symmetrical involvement of multiple nerve trunks in all patients. Neuromuscular biopsy (performed in five patients) showed histological signs of vasculitis in two patients and perivascular lymphocytic inflammatory infiltrates in two others. All patients were treated with glucocorticosteroids combined with cyclophosphamide (n = 6), rituximab (n = 3), or mycophénolate-mofétil (n = 1). The median follow-up was 5 years. Two patients relapsed during follow-up. All patients had motor and/or sensory sequelae upon follow-up. MM associated with SLE is frequently caused by a vasculitis mechanism. Patients improve with steroids and immunosuppressive drugs. Long-term outcomes include frequent clinical sequelae and possible relapses.

Mononeuritis multiplex in a patient with cutaneous arteritis diagnosed by skin biopsy.

A 55-year-old man was admitted with paralysis of the left lower leg. He had purpura in the left lower extremity for three years, left calf pain for two years, and dysesthesia in the left plantar region and first toe for one year. A physical examination revealed livedo reticularis on the left leg and mononeuritis multiplex was diagnosed in the bilateral tibial and left peroneal nerve area. Anti-neutrophil cytoplasmic antibody was negative. A nerve conduction study showed decreased amplitude of compound muscle-action potential in the bilateral tibial and the left peroneal nerve, sensory nerve action potential in the bilateral sural nerve. A skin biopsy revealed inflammatory cells on blood vessel walls and cutaneous arteritis was diagnosed. Cyclophosphamide pulse therapy with steroid and anti-coagulation improved the neurological symptoms. A skin biopsy should be considered when patients present with mononeuritis multiplex in the lower extremities and cutaneous findings such as livedo reticularis in the symptomatic area.

Pins and Needles From Fingers to Toes: High-Resolution MRI of Peripheral Sensory Mononeuropathies.

OBJECTIVE: The purpose of this article is to review advanced MRI techniques and describe the MRI findings of pure sensory mononeuropathy with relevant clinical and anatomic correlation. CONCLUSION: Peripheral sensory mononeuropathy can be challenging to evaluate with MRI because of the small caliber of pure sensory nerves and the lack of changes in secondary muscular denervation. Advances in MRI afford the necessary signal-intensity contrast and resolution for adequate evaluation of many of these small peripheral nerves.

Transcriptional expression of inflammatory mediators in various somatosensory relay centers in the brain of rat models of peripheral mononeuropathy and local inflammation.

Contradictory results have been reported regarding the role of inflammatory mediators in the central nervous system in mediating neuropathic pain and inflammatory hyperalgesia following peripheral nerve injury or localized inflammation. The present study aims to correlate between the mRNA expression and protein secretion of proinflammatory cytokines and nerve growth factor (NGF), in the dorsal root ganglia (DRGs), spinal cord, brainstem and thalamus, and pain-related behavior in animal models of peripheral mononeuropathy and localized inflammation. Different groups of rats (n=8, each) were subjected to either lesion of the nerves of their hindpaws to induce mononeuropathy or intraplantar injection of endotoxin (ET) and were sacrificed at various time intervals. TNF-α, IL-1ß and NGF mRNA expression and protein levels in the various centers involved in processing nociceptive information were determined, by RT-PCR and ELISA. Control groups were either subjected to sham surgery or to saline injection. Mononeuropathy and ET injection produced significant and sustained increases in the mRNA expression and protein levels of TNF-α, IL-1ß and NGF in the ipsilateral and contralateral DRGs, spinal cord, and brainstem. No significant and consistent changes in the mRNA expression of cytokines were noticed in the thalamus, while a downregulation of the NGF-mRNA level was observed. The temporal and spatial patterns of the observed changes in mRNA expression of cytokines and NGF are not closely in phase with the observed allodynia and hyperalgesia in the different models, suggesting that the role of these mediators may not be reduced exclusively to the production and maintenance of pain.

[Mononeuritis multiplex due to thrombotic ischemia of primary antiphospholipid antibody syndrome without vasculitis: an autopsy case report].

The patient was a 78-year-old man. Three years before admission, he developed transient peripheral neuropathy and purpura, and at admission, he presented with livedo reticularis of both his lower extremities and with mononeuritis multiplex. Vasculitis was not observed, and antiphospholipid antibodies were detected. The nerve and skin biopsies revealed no inflammation; axonal degeneration accompanied by thrombi was found in his arterioles and venules. Based on these findings, he was diagnosed with ischemic peripheral neuropathy due to primary antiphospholipid syndrome. Administration of anticoagulant therapy resulted in an improvement in symptoms; however, two months later, a relapse occurred, and the patient contracted an infection while undergoing immunosuppressive therapy. The infection became fulminant, and the patient succumbed to multiple organ failure. The autopsy revealed a systemic arterial and venous embolism; however, no vasculitis was observed. Antiphospholipid syndrome, which is responsive to antithrombotic treatment, should be considered as a differential diagnosis of mononeuritis multiplex.

Sural mononeuropathy: a report of 36 cases.

INTRODUCTION: Isolated sural mononeuropathy is rare and frequently constitutes a diagnostic challenge. METHODS: This investigation was a retrospective study of sural neuropathy at a single electrodiagnostic center. RESULTS: Our study included 36 patients with sural neuropathy, the largest sample so far reported. Non-surgical, non-traumatic etiologies account for 50% of the cases, including 7 patients with inflammatory or vasculitic conditions. Routine sural conduction study was positive in 34 of 36 patients, whereas a distal recording method was used to verify the diagnosis of sural mononeuropathy in 2 patients. Most (58%) patients did not require specific treatment, but persistent sensory symptoms were seen in a minority of cases. Sural nerve biopsy in 1 patient helped diagnostic and treatment planning. CONCLUSIONS: Sural mononeuropathy has distinct etiologic, clinical, and electrophysiological features. Recognition can be beneficial in treating patients with sensory symptoms involving the distal lower extremity.

Mononeuritis multiplex with tumefactive cellular infiltration in a patient with reactive lymphoid hyperplasia with increased immunoglobulin G4-positive cells.

We describe a 54-year-old man with mononeuritis multiplex and reactive lymphoid hyperplasia with increased immunoglobulin G4 (IgG4)-positive cells. Asymmetrical numbness and weakness had advanced stepwise for 6 years. Serum immunoglobulin G, IgG4, and immunoglobulin E levels were elevated, whereas M protein was not detected. Chest and abdominal computed tomography showed generalized lymphadenopathy. Inguinal lymph node biopsy revealed expansion of the interfollicular area with infiltration of IgG4-positive cells, of which the absolute number was greater than 100 per high-power field, and the percentage of IgG4+/immunoglobulin G+ plasma cells was 33%. Sural nerve biopsy disclosed axonal neuropathy with tumefactive lymphoid infiltrate in epineurium, but IgG4-positve plasma cells and fibrosis were not detected. Symptoms and laboratory data were improved with oral glucocorticoid therapy at a dose of 0.6 mg/kg per day. Although the causal mechanisms of neuropathy should be determined in future studies, peripheral nerve involvement may occur in patients with reactive lymphoid hyperplasia with increased IgG4-positive cells.

Mononeuritis multiplex in a patient with B-cell prolymphocytic leukaemia: a diagnostic challenge.

B-cell prolymphocytic leukaemia (BPLL) is a haematological malignancy defined as lymphocytosis and splenomegaly with >55% circulating cells being clonal prolymphocytes of B-cell origin. The evolution of this disease is more aggressive than chronic lymphocytic leukaemia. We reported a case of a 62-year-old man with BPLL who, on treatment, attained cytological, immunophenotypic and complete cytogenetic remission. He subsequently developed an asymmetric sensorimotor neurological disorder, suggestive of lymphomatous infiltration (neurolymphocytosis). Repetition of the MRI and the electromyography was essential for diagnosis. Progressive mononeuritis multiplex in B-cell leukaemias/lymphomas is rare and may be the only presenting symptom of relapsed or progressive disease. Repeat imaging studies based on judicious evaluation of the clinical scenario for exclusion of other causes of neurological symptoms is necessary. This can be challenging in patients with long-standing malignancies who have received multiple courses of chemotherapy and/or radiotherapy.

Epithelioid sarcoma presenting as radial mononeuropathy: anatomical, magnetic resonance neurography and diffusion tensor imaging appearances.

The authors report an unusual case of radial mononeuropathy caused by epithelioid sarcoma and describe the anatomical 3-Tesla MR neurography and the functional diffusion tensor imaging findings of the case, which were subsequently confirmed on surgical excision and histopathology.

An unusual cause of mononeuritis multiplex.

A middle-aged man of South Asian decent presented with a 4-month history of bilateral sensory disturbance affecting the median nerve distribution and dorsum of both feet. Neurological examination was otherwise normal. A patchy absence of sensory responses was noted on nerve conduction studies and electromyogram (NCS/EMG). Over the next 3 months sensory symptoms progressed to involve median, radial, ulnar, sural and peroneal nerves bilaterally. Repeat NCS/EMG confirmed a mononeuritis multiplex predominantly involving the sensory fascicles. Areas of hypopigmentation, a right-lower motor facial weakness and ophthalmic branch trigeminal nerve involvement were noted on examination. Punch skin biopsy as well as sural nerve biopsy demonstrated chronic granulomatous inflammation without evidence of Mycobacterium. A slit skin smear test demonstrated Mycobacterium leprae consistent with a diagnosis of primary neuritic leprosy. In the appropriate clinical context, leprosy should be included in the differential diagnosis of mononeuritis multiplex.

Uncommon pathological findings in sural nerve biopsy from a patient with Churg-Strauss related multiple mononeuropathy.

We describe a patient with severe multiple mononeuropathy associated with hypereosinophilia, asthma and pulmonary non cavitating micronodules. Sural nerve biopsy revealed marked perineural thickening and microfasciculation with inflammatory infiltrates in the perinerium and in the epinerium. The patient markedly improved with steroid therapy. Our final diagnosis was Churg-Strauss related multiple mononeuropathy. Thus, we report a case of Churg-Strauss related multiple mononeuropathy with uncommon pathological findings on sural nerve and we underline the importance of clinical evaluation for this diagnosis.

MRI in hypertrophic mono- and polyneuropathies.

Different conditions that may lead to enlarged nerves or nerve roots include hereditary motor and sensory neuropathy (HMSN), neurofibromatosis (NF) type 1, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and intraneural perineurioma. Differential diagnosis of hypertrophic mono- and polyradiculopathies remains challenging but is important because of different treatments and prognosis. Magnetic resonance imaging (MRI) can identify the hypertrophic nerve segments and guide a fascicular biopsy. A fascicular biopsy will often be necessary for precise diagnosis.

Sensory neuropathy may cause central neuronal reorganization but does not respecify perceptual quality or localization of sensation.

OBJECTIVES: Functional reorganization in the somatosensory network after peripheral nerve lesions has been suspected to modify the clinical expression of symptoms. However, no conclusive evidence exists to support this notion. We addressed this question by investigating the topographic distribution of the subjective sensory report in various chronic human mononeuropathies. METHODS: We report the clinical results of 86 patients who were diagnosed with meralgia paresthetica, 86 patients with ulnar neuropathy at the elbow, and 203 patients with carpal tunnel syndrome. RESULTS: In the carpal tunnel syndrome group, 10% of the patients exhibited a spread of sensory symptoms beyond the innervation territory of the median nerve. As previously reported, this spread was contingent upon an indirect compressive lesion of the ulnar nerve at the wrist. In all of the patients who were affected with meralgia paresthetica or ulnar neuropathy at the elbow, the peripheral referral of sensation was always within the anatomic distribution of the affected nerve. DISCUSSION: In human neuropathies, the projected sensory symptoms are restricted to the innervation territories of the affected nerves, with no extraterritorial spread. Thus, the somatosensory localization function remains accurate, despite the central reorganization that presumably occurs after nerve injury. We conclude that reorganization of the sensory connections within the central nervous system after peripheral nerve injury in humans is a clinically silent adaptive phenomenon.