Original Article
Journal of
CLINICAL NEUROMUSCULAR DISEASE
125
Volume 16, Number 3 March 2015
Eosinophilic Granulomatosis With Polyangiitis (Churg–Strauss Syndrome) Presenting With Polyneuropathy—A Case Series Fernando Santos-Pinheiro, MD and Yuebing Li, MD, PhD
Abstract Objectives: We aim to characterize a group of patients with eosinophilic granulomatosis with polyangiitis (EGPA) with an initial presentation of peripheral neuropathy. Methods: A retrospective analysis of 11 patients with EGPA. Results: The most common chief complaint was neuropathic limb pain and numbness (100%), followed by extremity weakness (82%). Nine (82%) patients had acute to subacute onset. All patients had a history of asthma and serum eosinophilia of more than 11%. Combining clinical and electrophysiological data, 10 (91%) patients demonstrated notable asymmetric involvement, whereas 1 patient presented with a length-dependent symmetrical axonal polyneuropathy. All patients improved significantly after immunotherapy, with average time to improvement of 9 weeks. Ten (91%) patients improved steadily and experienced no relapse, whereas 1 relapsed within the first year. Conclusions: EGPA should be suspected in patients with asymmetric axonal peripheral neuropathy associated with asthma and eosinophilia. Early diagnosis and aggressive treatment help to achieve favorable outcome. Key Words: vasculitic neuropathy, vasculitis, eosinophilic granulomatosis with polyangiitis, Churg– Strauss syndrome, mononeuropathy multiplex
( J Clin Neuromusc Dis 2015;16:125–130)
INTRODUCTION Eosinophilic granulomatosis with polyangiitis (EGPA) or Churg–Strauss syndrome is a rare autoimmune condition affecting multiple organs. The diagnosis of EGPA is mostly based
on the classification criteria agreed by the American College of Rheumatology, which requires 4 of 6 of the following features: asthma, blood eosinophilia greater than 10%, fleeting pulmonary infiltrates, paranasal sinus abnormality, mononeuropathy or polyneuropathy, and extravascular eosinophil infiltration on biopsy specimen.1 Neurological symptoms can be seen in 60%–70% of patients with EGPA, secondary only to pulmonary manifestations in the overall frequency of organ involvement.2 Some of the neurological manifestations in EGPA include cranial neuropathy, extremity mononeuropathy, mononeuropathy multiplex, symmetrical length-dependent polyneuropathy, and rarely manifestation of central nervous system dysfunction.3,4 In a portion of cases, neurological dysfunction may precede the involvement of other organs or be part of the presenting constellation.5 Therefore, neurologists could be among the first to evaluate or diagnose EGPA patients. An early recognition of this entity is the key in leading to timely treatment and favorable outcome. This case series aimed to retrospectively analyze a group of patients with EGPA whose initial presentation encompassing neurologic symptoms. All patients were first seen in neurology or neuromuscular clinic and diagnosed with EGPA later on. All cases received a detailed neurological examination at the disease onset. Our aims were: (1) to characterize the subgroup of patients with neurological presentation to identify possible features to assist the EGPA diagnosis, and (2) to summarize
From the Department of Neurology, Cleveland Clinic Foundation, Cleveland, OH. The authors report no conflicts of interest. Reprints: Yuebing Li, MD, PhD, Department of Neurology, Neuromuscular Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195 (e-mail: [email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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the treatment response and long-term prognosis in this subgroup of patients.
METHODS The study was approved by the Institutional Review Board from Cleveland Clinic. Recruitment was made upon chart review of all patients from January 1, 2000, to May 31, 2013, who had a confirmed diagnosis of EGPA. Patients were selected based on the following inclusion criteria: (1) patient initially presented with a chief complaint of neurological symptoms and was seen by a boardcertified neurologist or neuromuscular specialist, (2) patient was later diagnosed with EGPA by a board-certified rheumatologist based on clinical and/or pathological criteria set up by the American College of Rheumatology,1 (3) patient had at least 3 subsequent follow-up visits, and (4) patient had electrodiagnostic studies as part of the initial diagnostic workup. Retrospective review of electronic medical records was conducted by and data entry was agreed upon between both authors. Acute presentation was defined when a patient was evaluated within 1 month of symptom onset. Subacute presentation was defined when patient’s symptomatic duration was between 1 and 3 months before evaluation. Chronic onset was defined when the patient’s symptomatic duration was longer than 3 months at the initial presentation. All motor and sensory nerve conduction studies were performed using standard technique of surface stimulation and recording, and needle electromyography was performed using concentric needle electrode. In all patients, motor nerve conduction studies included median, ulnar, peroneal (fibular), and tibial nerves; sensory nerve conduction studies included median, ulnar, radial, and sural nerves; and needle examination was performed in the proximal and distal muscles of upper and lower extremities ipsilateral to nerve conduction study. Unilateral electrodiagnostic study was performed on the more symptomatic side, and bilateral electrodiagnostic studies were conducted if clinically
necessary. Asymmetry on nerve conduction study is defined when the evoked sensorimotor response is less than 50% of the contralateral side. The pattern of neuropathy was described as axonal or demyelinating, polyneuropathy, or mononeuropathy multiplex.
RESULTS During the study period, a total of 28 EGPA cases were encountered, 17 of whom presented with neuromuscular symptoms. Six of the 17 patients developed neuromuscular symptoms later during the course after the EGPA diagnosis was established, therefore excluded from this study. A total of 11 patients (5 males and 6 females) were included, with a mean age of 53 years (range, 45–63 years). Table 1 listed the demographic information and essential clinical features for all 11 patients. The most common chief complaint was neuropathic limb pain and numbness (100%). The distribution of neuropathic pain and numbness included upper extremity only (9%), lower extremity only (55%), and combined upper and lower extremities (36%). Nine (82%) patients had an acute to subacute onset, whereas 2 (18%) patients had a chronic progression before diagnosis. The average time from neurologic symptomatic onset to the EGPA diagnosis was 8 months (range, 1–36 months). All patients had a history of asthma, 7 (64%) of whom having carried the diagnosis for longer than 10 years. Four (36%) patients also possessed a history of chronic sinusitis. At presentation, 8 (73%) patients had accompanying symptoms of malaise or weight loss. On examination, 7 (64%) patients had cutaneous involvement in the form of purpura or maculopapular lesions. Five (45%) of 9 patients who underwent chest CT revealed findings consistent with diffuse parenchymal opacification. None had abnormal kidney function measured by glomerular filtration rate (normal .60 mL/min) although 5 (45%) patients showed microscopic hematuria on urinalysis. All patients had eosinophilia of more than 11% on peripheral blood analysis. Seven
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TABLE 1. Clinical Features of 11 Patients With EGPA
Number
Age (yrs)/ Sex
1
58, F
2
48, F
Presenting Symptom Pain and numbness in left forearm and both legs
EMG Finding polyneuropathy
Pain and numbness in mononeuropathy right more than left multiplex leg, then left more than right arm
Eosinophil Fraction (%) 60
84
Induction (I) and Maintenance (MA) Regime at Indicated Treatment Duration I: prednisone,
MA: prednisone of 6 mg/d at 42 mons I: prednisone, cyclophosphamide
3
47, F
Pain and numbness in polyneuropathy right then left leg
33
4
53, M
Pain and numbness in both legs
42
MA: azathioprine of 75 mg/d at 36 mons I: prednisone and cyclophosphamide MA: azathioprine of 125 mg/d at 68 mons I: prednisone
58
MA: methotrexate of 5 mg/wk I: prednisone
56
MA: prednisone of 30 mg/d at 10 mons I: prednisone
5
6
7
8
9
10
11
46, M
56, F
45, M
49, M
63, M
53, F
55, F
mononeuropathy multiplex
Pain and numbness in mononeuropathy feet, gait difficulty multiplex
Pain and numbness in polyneuropathy both feet, then left hand
Pain and numbness in mononeuropathy legs, gait difficulty multiplex
Pain and numbness in polyneuropathy feet and finger tips
Pain and numbness in polyneuropathy legs and left hand, right foot drop
Pain in both arms and hands
Pain in right leg, then both hands
mononeuropathy multiplex
polyneuropathy
5
MA: prednisone of 12.5 mg/d I: prednisone
12
MA: prednisone of 10 mg/d I: prednisone, IVIG
11
MA: azathioprine of 100 mg/d at 11 mons I: prednisone
43
MA: azathioprine of 100 mg/d In: prednisone
62
MA: prednisone at 10 mg/d I: prednisone, cyclophosphamide MA: prednisone at 5 mg/d azathioprine of 75 mg/d at 15 mons
EGPA, eosinophilic granulomatosis with polyangiitis; EMG, electromyography; I, induction; MA, maintenance.
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(63%) patients were also found mildly anemic (hemoglobin ,11 g/dL or hematocrit ,36%) on presentation. Antineutrophil cytoplasmic antibody (ANCA) was positive in 4 (36%) patients (perinuclear ANCA 2; cytoplasmic ANCA 2). Erythrocyte sedimentation rate was high (.45 mm/h) in 3 (27%) patients and C-reactive protein was abnormal (.5 mg/dL) in 5 (45%) patients. Creatine phosphokinase was high (.250 U/L) in 5 patients. Cerebrospinal fluid analyses in 3 patients were unremarkable. On neurologic examination, all patients had sensory loss in the upper and/or lower extremities, 4 (36%) being asymmetric. All patients had decreased or absent extremity reflexes, 9 (82%) of whom presented asymmetrically. Manual strength examination revealed muscle weakness in 9 (82%) patients, 4 being asymmetric. Nerve conduction study and electromyography were performed bilaterally in 6 patients and unilaterally in the remaining 5 patients. Electrodiagnostic findings consistent with a mononeuropathy multiplex pattern were evident in 5 (45%) patients, and a pattern of polyneuropathy was seen in the remaining 6 (55%) patients. All patients demonstrated evidence of axonal loss rather than demyelinating changes on electrophysiological studies. Among individual nerve involvement, peroneal (fibular) and tibial (9 patients, 82% each) nerves were the most commonly affected, followed by median and ulnar nerves (6 patients, 54% each). Combining clinical and electrophysiological data, 10 (91%) patients demonstrated notable asymmetric involvement, whereas 1 patient had a length-dependent sensorimotor polyneuropathy. Three patients (patients 2, 5, and 9 in Table 1) were submitted to sural nerve biopsy. Patients 2 and 9 received combined sural and lateral gastrocnemius muscle biopsies. In both patients, sural nerve biopsy revealed findings of necrotizing vasculitis, and muscle biopsy revealed findings of grouped fiber atrophy only. In patient 5, a sural nerve biopsy demonstrated axonal loss and muscle biopsy was not performed. None of the muscle or nerve biopsies demonstrated granulomatous formation or
eosinophil infiltration. Two additional patients (patients 1 and 4) had transbronchial biopsy revealing eosinophilic infiltration in the bronchial mucosa and 1 patient (patient 10) demonstrated increased eosinophil fraction in the bone marrow aspiration. No tissue biopsy was performed in the remaining 5 patients. The average follow-up period was 33 months (range, 10–132 months). For induction treatment, all patients received prednisone at dosages of 60 mg/d or higher followed by cyclophosphamide (8 patients), rituximab (1 patient), or intravenous immunoglobulin (1 patient). For maintenance treatment, prednisone (11 patients) and azathioprine (8 patients) were the preferred agents, followed by mycophenolate (3 patients) and methotrexate (2 patients). Five (45%) patients required a combination of 4 or more immunosuppressive agents to achieve a stably improved clinical state. The eventual long-term maintenance therapy included prednisone (7 patients), azathioprine (6 patients), mycophenolate (3 patients), and methotrexate (1 patient). All patients improved significantly after immunosuppressive treatment, with average time to improvement of 9 weeks after initiation of treatment (range, 2–32 weeks). Pain was usually the first improved symptom. Ten (91%) patients improved steadily and experienced no relapse over the follow-up period, whereas 1 had a relapse within the first year after an initial improvement. At the final follow-up, 2 (18%) patients had a normal neurological examination, whereas 9 (82%) patients still exhibited mostly mild neurological deficits.
DISCUSSION An early recognition of EGPA is important as its remission relies on the early initiation of immunosuppressive therapy. Previously, a number of case report or series focused on the characterization of neurological manifestation in patients with EGPA.3–8 Although these publications contributed significantly to the literature, some had limitations. For example, the characterization of
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Eosinophilic Granulomatosis
neuropathy in EGPA usually included description of cases occurring both at the disease onset and during disease progression. However, neuropathy developing at a later stage may not be EGPA-specific, as their occurrence could be secondary to coexisting etiologies, such as comorbidity, local compression, or medication toxicity.9 Additionally, evolutional changes are often observed in vasculitic neuropathy. At a later stage, vasculitic neuropathy tends to exhibit symmetric polyneuropathy instead of mononeuropathy multiplex.10,11 Our study focus was to identify clinical features that are suggestive of EGPA for the subgroup of patients with an initial neurologic presentation. The spectrum of clinical manifestation seen in our patients was similar to that of published series.5,6,11 Asthma of usually long duration was the most frequently encountered history, whereas hypereosinophilia was the main laboratory finding. Both features were universally present among all patients. Several other features were quite helpful as diagnostic clues, namely acute to subacute presentation, fatigue and weight loss, cutaneous lesion, microscopic hematuria, and anemia. The main neurological manifestation in our patients was asymmetric peripheral polyneuropathy, which is in accordance with the literature.5,11 Acute to subacute painful polyneuropathy was the most common presentation. The high rate (91%) of asymmetric polyneuropathy in our patients is possibly because of early diagnosis. In our group, a total of 3 nerve biopsies were performed, 2 of which showed findings consistent with necrotizing vasculitis. Additionally, extravascular eosinophil infiltration was seen in 3 patients on transbronchial biopsy or bone marrow aspiration. These findings highlighted the importance of precise histological examination in establishing the EGPA diagnosis. Nevertheless, the successful diagnosis and treatment of EGPA in the remaining 5 patients without the need of biopsy indicated that the biopsy procedure may not be mandatory in some patients with EGPA with characteristic clinical findings.
A sural nerve biopsy or a sural nerve and lateral gastrocnemius combined biopsy approach was adopted in this study. However, it is worth mentioning that a combined superficial peroneal nerve and peroneus brevis muscle biopsy offers excellent diagnostic yield and might be the preferred approach in the diagnosis of vasculitic neuropathy including neuropathy in EGPA.12 Treatment options for vasculitic neuropathy may vary according to the severity and extent of the disease. Guidelines recommend that corticosteroid as the main therapy, whereas patients with more extended organ involvement and/or disease severity may require a combination of corticosteroid and cyclophosphamide or rituximab.13,14 The treatment strategy for induction in our group is consistent with the guideline, with most patients having received high-dose corticosteroid and cyclophosphamide, whereas IVIG and rituximab were used in 2 patients. The overall treatment response and prognosis were very favorable in this group of 11 patients with EGPA. A rather fast recovery (mean interval of 9 weeks) was observed after initiation of immunosuppressive therapy. Relapses were not seen in the majority of patients with a mean follow-up period of 33 months after initiation of treatment. The low incidence of relapse and the presence of favorable outcome in our group underline the generally good prognosis of EGPA when diagnosed and treated early, as previously reported.4,15 However, medication usage and treatment response were still variable among this group of patients. Approximately, half of the patients in this series required a trial of 4 or more agents to achieve improvement and stabilization of symptoms. The usage of multiple agents in these patients was secondary to lack of efficacy and/or development of side effects. An appropriate evaluation of the EGPA responsiveness to immunotherapy will probably require a controlled treatment trial. Notwithstanding of limitations of small number of cases, monocentric experience, and respective analysis, our study indicate
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that a suspicion for EGPA should be raised for patients presenting with asymmetric painful peripheral neuropathy with asthma and eosinophilia, and a more refined workup including histological examination should be pursued. Once diagnosed, these patients should be treated aggressively with commonly used immunosuppressive therapy, and favorable outcome is usually expected in the majority of patients. REFERENCES 1. Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum. 1990;33: 1094–1100. 2. Gwathmey KG, Burns TM, Collins MP, et al. Vasculitic neuropathies. Lancet Neurol. 2014;13:67–82. 3. Sehgal M, Swanson JW, DeRemee RA, et al. Neurologic manifestations of Churg-Strauss syndrome. Mayo Clin Proc. 1995;70:337–341. 4. Wolf J, Bergner R, Mutallib S, et al. Neurologic complications of Churg-Strauss syndrome–a prospective monocentric study. Eur J Neurol. 2010;17:582–588. 5. Wolf J, Schmitt V, Palm F, et al. Peripheral neuropathy as initial manifestation of primary systemic vasculitides. J Neurol. 2013;260:1061–1070. 6. Hattori N, Ichimura M, Nagamatsu M, et al. Clinicopathological features of Churg-Strauss syndrome-associated neuropathy. Brain. 1999;122(Pt 3):427–439.
7. Cattaneo L, Chierici E, Pavone L, et al. Peripheral neuropathy in Wegener’s granulomatosis, ChurgStrauss syndrome and microscopic polyangiitis. J Neurol Neurosurg Psychiatry. 2007;78:1119–1123. 8. Bonaventura Ibars I, de Francisco Moure J, Pineda Barrero S, et al. Peripheral polyneuropathy and Churg-Strauss syndrome. Neurologia. 2014;29: 249–250. 9. Suppiah R, Hadden RD, Batra R, et al. Peripheral neuropathy in ANCA-associated vasculitis: outcomes from the European Vasculitis Study Group trials. Rheumatology (Oxford). 2011;50:2214–2222. 10. Davies L, Spies JM, Pollard JD, et al. Vasculitis confined to peripheral nerves. Brain. 1996;119(Pt 5): 1441–1448. 11. Kararizou E, Davaki P, Spengos K, et al. ChurgStrauss syndrome complicated by neuropathy: a clinicopathological study of nine cases. Clin Neuropathol. 2011;30:11–17. 12. Agadi JB, Raghav G, Mahadevan A, et al. Usefulness of superficial peroneal nerve/peroneus brevis muscle biopsy in the diagnosis of vasculitic neuropathy. J Clin Neurosci. 2012;19:1392–1396. 13. Bosch X, Guilabert A, Espinosa G, et al. Treatment of antineutrophil cytoplasmic antibody associated vasculitis: a systematic review. JAMA. 2007;298: 655–669. 14. Ntatsaki E, Carruthers D, Chakravarty K, et al. BSR and BHPR guideline for the management of adults with ANCA-associated vasculitis. Rheumatology (Oxford). 2014;53:2306–2309. 15. Nakamura M, Yabe I, Yaguchi H, et al. Clinical characterization and successful treatment of 6 patients with Churg-Strauss syndrome-associated neuropathy. Clin Neurol Neurosurg. 2009;111:683–687.
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Journal of
CLINICAL NEUROMUSCULAR DISEASE
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Volume 16, Number 3 March 2015
Eosinophilic Granulomatosis With Polyangiitis (Churg–Strauss Syndrome) Presenting With Polyneuropathy—A Case Series Fernando Santos-Pinheiro, MD and Yuebing Li, MD, PhD
Abstract Objectives: We aim to characterize a group of patients with eosinophilic granulomatosis with polyangiitis (EGPA) with an initial presentation of peripheral neuropathy. Methods: A retrospective analysis of 11 patients with EGPA. Results: The most common chief complaint was neuropathic limb pain and numbness (100%), followed by extremity weakness (82%). Nine (82%) patients had acute to subacute onset. All patients had a history of asthma and serum eosinophilia of more than 11%. Combining clinical and electrophysiological data, 10 (91%) patients demonstrated notable asymmetric involvement, whereas 1 patient presented with a length-dependent symmetrical axonal polyneuropathy. All patients improved significantly after immunotherapy, with average time to improvement of 9 weeks. Ten (91%) patients improved steadily and experienced no relapse, whereas 1 relapsed within the first year. Conclusions: EGPA should be suspected in patients with asymmetric axonal peripheral neuropathy associated with asthma and eosinophilia. Early diagnosis and aggressive treatment help to achieve favorable outcome. Key Words: vasculitic neuropathy, vasculitis, eosinophilic granulomatosis with polyangiitis, Churg– Strauss syndrome, mononeuropathy multiplex
( J Clin Neuromusc Dis 2015;16:125–130)
INTRODUCTION Eosinophilic granulomatosis with polyangiitis (EGPA) or Churg–Strauss syndrome is a rare autoimmune condition affecting multiple organs. The diagnosis of EGPA is mostly based
on the classification criteria agreed by the American College of Rheumatology, which requires 4 of 6 of the following features: asthma, blood eosinophilia greater than 10%, fleeting pulmonary infiltrates, paranasal sinus abnormality, mononeuropathy or polyneuropathy, and extravascular eosinophil infiltration on biopsy specimen.1 Neurological symptoms can be seen in 60%–70% of patients with EGPA, secondary only to pulmonary manifestations in the overall frequency of organ involvement.2 Some of the neurological manifestations in EGPA include cranial neuropathy, extremity mononeuropathy, mononeuropathy multiplex, symmetrical length-dependent polyneuropathy, and rarely manifestation of central nervous system dysfunction.3,4 In a portion of cases, neurological dysfunction may precede the involvement of other organs or be part of the presenting constellation.5 Therefore, neurologists could be among the first to evaluate or diagnose EGPA patients. An early recognition of this entity is the key in leading to timely treatment and favorable outcome. This case series aimed to retrospectively analyze a group of patients with EGPA whose initial presentation encompassing neurologic symptoms. All patients were first seen in neurology or neuromuscular clinic and diagnosed with EGPA later on. All cases received a detailed neurological examination at the disease onset. Our aims were: (1) to characterize the subgroup of patients with neurological presentation to identify possible features to assist the EGPA diagnosis, and (2) to summarize
From the Department of Neurology, Cleveland Clinic Foundation, Cleveland, OH. The authors report no conflicts of interest. Reprints: Yuebing Li, MD, PhD, Department of Neurology, Neuromuscular Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195 (e-mail: [email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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the treatment response and long-term prognosis in this subgroup of patients.
METHODS The study was approved by the Institutional Review Board from Cleveland Clinic. Recruitment was made upon chart review of all patients from January 1, 2000, to May 31, 2013, who had a confirmed diagnosis of EGPA. Patients were selected based on the following inclusion criteria: (1) patient initially presented with a chief complaint of neurological symptoms and was seen by a boardcertified neurologist or neuromuscular specialist, (2) patient was later diagnosed with EGPA by a board-certified rheumatologist based on clinical and/or pathological criteria set up by the American College of Rheumatology,1 (3) patient had at least 3 subsequent follow-up visits, and (4) patient had electrodiagnostic studies as part of the initial diagnostic workup. Retrospective review of electronic medical records was conducted by and data entry was agreed upon between both authors. Acute presentation was defined when a patient was evaluated within 1 month of symptom onset. Subacute presentation was defined when patient’s symptomatic duration was between 1 and 3 months before evaluation. Chronic onset was defined when the patient’s symptomatic duration was longer than 3 months at the initial presentation. All motor and sensory nerve conduction studies were performed using standard technique of surface stimulation and recording, and needle electromyography was performed using concentric needle electrode. In all patients, motor nerve conduction studies included median, ulnar, peroneal (fibular), and tibial nerves; sensory nerve conduction studies included median, ulnar, radial, and sural nerves; and needle examination was performed in the proximal and distal muscles of upper and lower extremities ipsilateral to nerve conduction study. Unilateral electrodiagnostic study was performed on the more symptomatic side, and bilateral electrodiagnostic studies were conducted if clinically
necessary. Asymmetry on nerve conduction study is defined when the evoked sensorimotor response is less than 50% of the contralateral side. The pattern of neuropathy was described as axonal or demyelinating, polyneuropathy, or mononeuropathy multiplex.
RESULTS During the study period, a total of 28 EGPA cases were encountered, 17 of whom presented with neuromuscular symptoms. Six of the 17 patients developed neuromuscular symptoms later during the course after the EGPA diagnosis was established, therefore excluded from this study. A total of 11 patients (5 males and 6 females) were included, with a mean age of 53 years (range, 45–63 years). Table 1 listed the demographic information and essential clinical features for all 11 patients. The most common chief complaint was neuropathic limb pain and numbness (100%). The distribution of neuropathic pain and numbness included upper extremity only (9%), lower extremity only (55%), and combined upper and lower extremities (36%). Nine (82%) patients had an acute to subacute onset, whereas 2 (18%) patients had a chronic progression before diagnosis. The average time from neurologic symptomatic onset to the EGPA diagnosis was 8 months (range, 1–36 months). All patients had a history of asthma, 7 (64%) of whom having carried the diagnosis for longer than 10 years. Four (36%) patients also possessed a history of chronic sinusitis. At presentation, 8 (73%) patients had accompanying symptoms of malaise or weight loss. On examination, 7 (64%) patients had cutaneous involvement in the form of purpura or maculopapular lesions. Five (45%) of 9 patients who underwent chest CT revealed findings consistent with diffuse parenchymal opacification. None had abnormal kidney function measured by glomerular filtration rate (normal .60 mL/min) although 5 (45%) patients showed microscopic hematuria on urinalysis. All patients had eosinophilia of more than 11% on peripheral blood analysis. Seven
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TABLE 1. Clinical Features of 11 Patients With EGPA
Number
Age (yrs)/ Sex
1
58, F
2
48, F
Presenting Symptom Pain and numbness in left forearm and both legs
EMG Finding polyneuropathy
Pain and numbness in mononeuropathy right more than left multiplex leg, then left more than right arm
Eosinophil Fraction (%) 60
84
Induction (I) and Maintenance (MA) Regime at Indicated Treatment Duration I: prednisone,
MA: prednisone of 6 mg/d at 42 mons I: prednisone, cyclophosphamide
3
47, F
Pain and numbness in polyneuropathy right then left leg
33
4
53, M
Pain and numbness in both legs
42
MA: azathioprine of 75 mg/d at 36 mons I: prednisone and cyclophosphamide MA: azathioprine of 125 mg/d at 68 mons I: prednisone
58
MA: methotrexate of 5 mg/wk I: prednisone
56
MA: prednisone of 30 mg/d at 10 mons I: prednisone
5
6
7
8
9
10
11
46, M
56, F
45, M
49, M
63, M
53, F
55, F
mononeuropathy multiplex
Pain and numbness in mononeuropathy feet, gait difficulty multiplex
Pain and numbness in polyneuropathy both feet, then left hand
Pain and numbness in mononeuropathy legs, gait difficulty multiplex
Pain and numbness in polyneuropathy feet and finger tips
Pain and numbness in polyneuropathy legs and left hand, right foot drop
Pain in both arms and hands
Pain in right leg, then both hands
mononeuropathy multiplex
polyneuropathy
5
MA: prednisone of 12.5 mg/d I: prednisone
12
MA: prednisone of 10 mg/d I: prednisone, IVIG
11
MA: azathioprine of 100 mg/d at 11 mons I: prednisone
43
MA: azathioprine of 100 mg/d In: prednisone
62
MA: prednisone at 10 mg/d I: prednisone, cyclophosphamide MA: prednisone at 5 mg/d azathioprine of 75 mg/d at 15 mons
EGPA, eosinophilic granulomatosis with polyangiitis; EMG, electromyography; I, induction; MA, maintenance.
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(63%) patients were also found mildly anemic (hemoglobin ,11 g/dL or hematocrit ,36%) on presentation. Antineutrophil cytoplasmic antibody (ANCA) was positive in 4 (36%) patients (perinuclear ANCA 2; cytoplasmic ANCA 2). Erythrocyte sedimentation rate was high (.45 mm/h) in 3 (27%) patients and C-reactive protein was abnormal (.5 mg/dL) in 5 (45%) patients. Creatine phosphokinase was high (.250 U/L) in 5 patients. Cerebrospinal fluid analyses in 3 patients were unremarkable. On neurologic examination, all patients had sensory loss in the upper and/or lower extremities, 4 (36%) being asymmetric. All patients had decreased or absent extremity reflexes, 9 (82%) of whom presented asymmetrically. Manual strength examination revealed muscle weakness in 9 (82%) patients, 4 being asymmetric. Nerve conduction study and electromyography were performed bilaterally in 6 patients and unilaterally in the remaining 5 patients. Electrodiagnostic findings consistent with a mononeuropathy multiplex pattern were evident in 5 (45%) patients, and a pattern of polyneuropathy was seen in the remaining 6 (55%) patients. All patients demonstrated evidence of axonal loss rather than demyelinating changes on electrophysiological studies. Among individual nerve involvement, peroneal (fibular) and tibial (9 patients, 82% each) nerves were the most commonly affected, followed by median and ulnar nerves (6 patients, 54% each). Combining clinical and electrophysiological data, 10 (91%) patients demonstrated notable asymmetric involvement, whereas 1 patient had a length-dependent sensorimotor polyneuropathy. Three patients (patients 2, 5, and 9 in Table 1) were submitted to sural nerve biopsy. Patients 2 and 9 received combined sural and lateral gastrocnemius muscle biopsies. In both patients, sural nerve biopsy revealed findings of necrotizing vasculitis, and muscle biopsy revealed findings of grouped fiber atrophy only. In patient 5, a sural nerve biopsy demonstrated axonal loss and muscle biopsy was not performed. None of the muscle or nerve biopsies demonstrated granulomatous formation or
eosinophil infiltration. Two additional patients (patients 1 and 4) had transbronchial biopsy revealing eosinophilic infiltration in the bronchial mucosa and 1 patient (patient 10) demonstrated increased eosinophil fraction in the bone marrow aspiration. No tissue biopsy was performed in the remaining 5 patients. The average follow-up period was 33 months (range, 10–132 months). For induction treatment, all patients received prednisone at dosages of 60 mg/d or higher followed by cyclophosphamide (8 patients), rituximab (1 patient), or intravenous immunoglobulin (1 patient). For maintenance treatment, prednisone (11 patients) and azathioprine (8 patients) were the preferred agents, followed by mycophenolate (3 patients) and methotrexate (2 patients). Five (45%) patients required a combination of 4 or more immunosuppressive agents to achieve a stably improved clinical state. The eventual long-term maintenance therapy included prednisone (7 patients), azathioprine (6 patients), mycophenolate (3 patients), and methotrexate (1 patient). All patients improved significantly after immunosuppressive treatment, with average time to improvement of 9 weeks after initiation of treatment (range, 2–32 weeks). Pain was usually the first improved symptom. Ten (91%) patients improved steadily and experienced no relapse over the follow-up period, whereas 1 had a relapse within the first year after an initial improvement. At the final follow-up, 2 (18%) patients had a normal neurological examination, whereas 9 (82%) patients still exhibited mostly mild neurological deficits.
DISCUSSION An early recognition of EGPA is important as its remission relies on the early initiation of immunosuppressive therapy. Previously, a number of case report or series focused on the characterization of neurological manifestation in patients with EGPA.3–8 Although these publications contributed significantly to the literature, some had limitations. For example, the characterization of
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Eosinophilic Granulomatosis
neuropathy in EGPA usually included description of cases occurring both at the disease onset and during disease progression. However, neuropathy developing at a later stage may not be EGPA-specific, as their occurrence could be secondary to coexisting etiologies, such as comorbidity, local compression, or medication toxicity.9 Additionally, evolutional changes are often observed in vasculitic neuropathy. At a later stage, vasculitic neuropathy tends to exhibit symmetric polyneuropathy instead of mononeuropathy multiplex.10,11 Our study focus was to identify clinical features that are suggestive of EGPA for the subgroup of patients with an initial neurologic presentation. The spectrum of clinical manifestation seen in our patients was similar to that of published series.5,6,11 Asthma of usually long duration was the most frequently encountered history, whereas hypereosinophilia was the main laboratory finding. Both features were universally present among all patients. Several other features were quite helpful as diagnostic clues, namely acute to subacute presentation, fatigue and weight loss, cutaneous lesion, microscopic hematuria, and anemia. The main neurological manifestation in our patients was asymmetric peripheral polyneuropathy, which is in accordance with the literature.5,11 Acute to subacute painful polyneuropathy was the most common presentation. The high rate (91%) of asymmetric polyneuropathy in our patients is possibly because of early diagnosis. In our group, a total of 3 nerve biopsies were performed, 2 of which showed findings consistent with necrotizing vasculitis. Additionally, extravascular eosinophil infiltration was seen in 3 patients on transbronchial biopsy or bone marrow aspiration. These findings highlighted the importance of precise histological examination in establishing the EGPA diagnosis. Nevertheless, the successful diagnosis and treatment of EGPA in the remaining 5 patients without the need of biopsy indicated that the biopsy procedure may not be mandatory in some patients with EGPA with characteristic clinical findings.
A sural nerve biopsy or a sural nerve and lateral gastrocnemius combined biopsy approach was adopted in this study. However, it is worth mentioning that a combined superficial peroneal nerve and peroneus brevis muscle biopsy offers excellent diagnostic yield and might be the preferred approach in the diagnosis of vasculitic neuropathy including neuropathy in EGPA.12 Treatment options for vasculitic neuropathy may vary according to the severity and extent of the disease. Guidelines recommend that corticosteroid as the main therapy, whereas patients with more extended organ involvement and/or disease severity may require a combination of corticosteroid and cyclophosphamide or rituximab.13,14 The treatment strategy for induction in our group is consistent with the guideline, with most patients having received high-dose corticosteroid and cyclophosphamide, whereas IVIG and rituximab were used in 2 patients. The overall treatment response and prognosis were very favorable in this group of 11 patients with EGPA. A rather fast recovery (mean interval of 9 weeks) was observed after initiation of immunosuppressive therapy. Relapses were not seen in the majority of patients with a mean follow-up period of 33 months after initiation of treatment. The low incidence of relapse and the presence of favorable outcome in our group underline the generally good prognosis of EGPA when diagnosed and treated early, as previously reported.4,15 However, medication usage and treatment response were still variable among this group of patients. Approximately, half of the patients in this series required a trial of 4 or more agents to achieve improvement and stabilization of symptoms. The usage of multiple agents in these patients was secondary to lack of efficacy and/or development of side effects. An appropriate evaluation of the EGPA responsiveness to immunotherapy will probably require a controlled treatment trial. Notwithstanding of limitations of small number of cases, monocentric experience, and respective analysis, our study indicate
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that a suspicion for EGPA should be raised for patients presenting with asymmetric painful peripheral neuropathy with asthma and eosinophilia, and a more refined workup including histological examination should be pursued. Once diagnosed, these patients should be treated aggressively with commonly used immunosuppressive therapy, and favorable outcome is usually expected in the majority of patients. REFERENCES 1. Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum. 1990;33: 1094–1100. 2. Gwathmey KG, Burns TM, Collins MP, et al. Vasculitic neuropathies. Lancet Neurol. 2014;13:67–82. 3. Sehgal M, Swanson JW, DeRemee RA, et al. Neurologic manifestations of Churg-Strauss syndrome. Mayo Clin Proc. 1995;70:337–341. 4. Wolf J, Bergner R, Mutallib S, et al. Neurologic complications of Churg-Strauss syndrome–a prospective monocentric study. Eur J Neurol. 2010;17:582–588. 5. Wolf J, Schmitt V, Palm F, et al. Peripheral neuropathy as initial manifestation of primary systemic vasculitides. J Neurol. 2013;260:1061–1070. 6. Hattori N, Ichimura M, Nagamatsu M, et al. Clinicopathological features of Churg-Strauss syndrome-associated neuropathy. Brain. 1999;122(Pt 3):427–439.
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