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Ultrasonographic findings of proximal median neuropathy: A case series of suspected distal neuralgic amyotrophy
Journal of the Neurological Sciences 377 (2017) 1–5
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Clinical Short Communication
Ultrasonographic findings of proximal median neuropathy: A case series of suspected distal neuralgic amyotrophy Yoshikatsu Noda a, Kenji Sekiguchi a,⁎, Hideki Tokuoka a, Tetsuya Oda b, Hirotoshi Hamaguchi b, Fumio Kanda a, Tatsushi Toda a a b
Division of Neurology, Kobe University Graduate School of Medicine, Japan Department of Neurology, Kita-HARIMA Medical Center, Japan
a r t i c l e
i n f o
Article history: Received 1 September 2016 Received in revised form 21 March 2017 Accepted 22 March 2017 Available online 24 March 2017 Keywords: Ultrasonography Neuralgic amyotrophy Proximal median neuropathy Anterior interosseous nerve palsy Hourglass-like appearance
a b s t r a c t Spontaneous anterior interosseous nerve (AIN) palsy develops following the resolution of nerve pain, which may be considered as distal neuralgic amyotrophy. NA is assumed to have a complex etiology, but an autoimmune mechanism is likely involved. However, precise assessment of the lesion is challenging. We examined five consecutive patients with suspected spontaneous AIN palsy using ultrasonography. On electromyography, all patients exhibited denervation potentials in the muscles, not only in the AIN territory, but also in the proximal median nerve territory (e.g., the flexor carpi radialis or pronator teres). Ultrasonography of the median nerve demonstrated neural swelling at the proximal side of the medial epicondyle in four patients and an hourglasslike constriction of the nerve fascicle in three patients. Four patients were diagnosed with distal neuralgic amyotrophy; of these, three received intravenous immunoglobulin administration, but only limited beneficial effect was achieved in one patient with early stage disease. One patient showed significant median nerve hypertrophy on ultrasonography and was diagnosed with neurolymphomatosis following the detection of malignant lymphoma during a systemic survey. Our experience demonstrates that ultrasonography for proximal median neuropathy presenting as AIN palsy may be useful for the accurate lesion assessment. © 2017 Elsevier B.V. All rights reserved.
1. Introduction The anterior interosseous nerve (AIN) branches from the median nerve at the elbow and typically innervates the flexor pollicis longus, flexor digitorum profundus (including the index and sometimes the middle fingers), and pronator quadratus muscles. Weakness of these muscles leads to defective flexion of the distal phalanges of the thumb and index finger when the patient is asked to make the “OK” sign; this is known as the “tear drop sign.” Because there are many anatomical variations of the AIN, patients do not always present with typical palsy [1]. Known causes of non-traumatic AIN palsy include space-occupying lesions, compression neuropathy, and pronator teres syndrome; “spontaneous” AIN palsy is considered if medical history, physical examination, and imaging fail to reveal a clear cause. Spontaneous AIN palsy often manifests approximately 1–2 weeks after resolution of idiopathic
Abbreviations: AIN, anterior interosseous nerve; NA, neuralgic amyotrophy; IVIG, intravenous immunoglobulin; CMAPs, compound muscle action potentials; CSA, cross sectional area. ⁎ Corresponding author at: Division of Neurology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chou-ku, Kobe City, Hyogo 650-0017, Japan. E-mail address: [email protected] (K. Sekiguchi).
http://dx.doi.org/10.1016/j.jns.2017.03.037 0022-510X/© 2017 Elsevier B.V. All rights reserved.
nerve pain in the affected limb, which is a distal subtype of neuralgic amyotrophy (NA) [2]. NA is assumed to have a complex etiology involving autoimmune, mechanical, and genetic factors. Observations that symptoms are often preceded by an antecedent infection, vaccination, or immunomodulating treatment support the hypothesis that attacks are immunomediated, explaining the term “immune-mediated brachial plexopathy” preferred by some, but no clear pathological mechanism has been identified [3]. Given the many uncertainties surrounding AIN palsy, there is no current consensus on an appropriate therapeutic protocol. Neurolysis has been reported as an effective treatment option, and given the potential involvement of inflammatory processes, immunotherapies such as corticosteroids or intravenous immunoglobulin (IVIG) are often administered [4,5]. In recent years, ultrasonography has been described as useful for diagnosing peripheral neuropathy. To further investigate these possible treatment modalities, we evaluated ultrasonographic findings of the peripheral nerve and clinical courses of patients with AIN palsy [6]. 2. Methods The subjects in this study were referred to our department between 2013 and 2015 for suspected spontaneous AIN palsy. We included five patients experiencing idiopathic focal pain in an upper limb and
2
Y. Noda et al. / Journal of the Neurological Sciences 377 (2017) 1–5
Fig. 1. Ultrasonograms of patient 1 showing side-to-side comparisons of the median nerve (circled). A: The 9-mm2 non-affected side (right arm) vs. B: cross-sectional area of the 18-mm2 affected side (left arm), in the region 5 cm proximal to the elbow. Lat: lateral, med: median.
subsequently decreased muscle strength in the fingers of the same limb (predominantly the flexor muscles of the thumb and index finger). The diagnosis was based on medical history, clinical examination, and ancillary investigations, such as magnetic resonance imaging of the cervical spine or lumbar puncture, to exclude other causes. All patients provided informed consent. Ultrasonography was performed using an APLIO™ 500 (Toshiba Medical Systems), a prosound α10 (Hitachi-Aloka Medical), and a 12–18 MHz linear probe. We identified the main trunk of the median nerve (including the branch of the AIN with the proximal part from the elbow) from the forearm to the upper arm region, and searched for the characteristic findings: neural swelling or hourglasslike constriction of the nerve branch. When the probe is lowered to the distal part of the constricted branch, it separates from the trunk of the median nerve in the pronator teres muscle and branches as the anterior interosseous nerve. To study nerve conduction, we applied surface electrodes to the abductor pollicis brevis, pronator quadratus, and flexor hallucis longus muscles. We then applied a supramaximal stimulus to the wrist and elbow regions of the median nerve and compared the bilateral compound muscle action potentials (CMAPs). The study met the guidelines of the Ethics Committee of Kobe University and was performed after informed consent was obtained. 3. Results 3.1. Patient 1 A 30-year-old man presented with pain extending from the left shoulder to the fingertips. Clinical examination revealed distal muscle
weakness and atrophy (pronator teres, pronator quadratus, flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, opponens pollicis, and abductor pollicis brevis). He did not report any shoulder region symptoms other than pain. There was no weakness or electromyographic abnormality in the proximal muscles (e.g., anterior serratus and supraspinatus muscles). Ultrasonography revealed neural swelling 5 cm proximal to the elbow (maximum cross sectional area [CSA]: 18 mm2; healthy side: 9 mm2), but there were no signs indicating hourglass-like constriction of the nerve fascicle (Fig. 1). Magnetic resonance imaging (MRI) of the left brachial plexus indicated normal signals. IVIG was administered 12 months after onset but had no effect. Subsequent neurolysis was somewhat effective in decreasing the patient's clinical symptoms.
3.2. Patient 2 A 46-year-old man presented with left shoulder pain. Clinical examination revealed distal muscle weakness (pronator quadratus, flexor digitorum profundus, and flexor pollicis longus). He did not report any shoulder region symptoms besides pain. There was no weakness or electromyographic abnormality in the proximal muscles. Ultrasonography revealed neural swelling 3 cm proximal to the elbow (maximum CSA: 20 mm2; healthy side: 9 mm2), and we suspected hourglass-like constriction of the nerve fascicle (Fig. 2). MRI of the left brachial plexus indicated normal signals. IVIG was administered 5 months after disease onset, and slight recovery of strength was observed in the flexor pollicis longus muscle 2 weeks later. Further gradual improvement of muscle
Fig. 2. Ultrasonograms of patient 2. A: Cross-sectional scans of the median nerve in the region 3 cm proximal to the elbow (cross-sectional area: 20 mm2). B: A longitudinal scan showing constriction of a fascicle of the median nerve at the elbow. Nerves with hourglass-like, incomplete constrictions and enlargements are shown. Dashed line: nerve epineurium, dotted line: nerve fascicle, arrowhead: hourglass-like constrictions, lat: lateral, med: median, dis: distal, prox: proximal.
Y. Noda et al. / Journal of the Neurological Sciences 377 (2017) 1–5
3
Fig. 3. Ultrasonograms of patient 3. A: Cross-sectional scans of the median nerve in the region 3 cm proximal to the elbow (cross-sectional area: 19 mm2). B: A longitudinal scan showing constriction of a fascicle of the median nerve at the elbow. Nerves with hourglass-like incomplete constrictions and enlargements are shown. Dashed line: nerve epineurium, dotted line: nerve fascicle, arrowhead: hourglass-like constrictions, lat: lateral, med: median, dis: distal, prox: proximal.
strength was observed, and complete remission was noted 7 months after disease onset. 3.3. Patient 3 A 47-year-old woman presented with left shoulder pain. Clinical examination revealed distal muscle weakness (pronator teres, pronator quadratus, flexor pollicis longus, flexor digitorum superficialis, flexor digitorum profundus, and flexor carpi radialis). She did not report any shoulder region symptoms other than pain. There was no weakness or electromyographic abnormality in the proximal muscles. Ultrasonography revealed neural swelling in the region 3 cm proximal to the elbow (maximum CSA: 19 mm2; healthy side: 10 mm2), and we suspected hourglass-like constriction of the nerve fascicle in this region (Fig. 3). MRI of the left brachial plexus indicated normal signals. IVIG was administered 7 months after onset, followed by neurolysis, but her symptoms did not improve. 3.4. Patient 4 A 58-year-old man presented with pain in the medial scapular region of the left shoulder. Clinical examination revealed distal muscle weakness (flexor pollicis longus, flexor digitorum superficialis, flexor digitorum profundus, extensor digitorum communis, first dorsal interosseous, and abductor digiti minimi). He did not report any shoulder region symptoms other than pain. There was no weakness or electromyographic abnormality in the proximal muscles. Ultrasonography revealed an hourglass-like constriction of the nerve fascicle 5 cm proximal to the elbow, and mild neural swelling was noted (maximum CSA: 17 mm2) (Fig. 4). MRI of the left brachial plexus indicated normal signals. Neurolysis was performed 6 months after onset, but the patient's symptoms did not improve.
3.5. Patient 5 A 46-year-old man presented with left middle finger pain. Clinical examination revealed distal muscle weakness (pronator quadratus, flexor digitorum profundus, and flexor pollicis longus). He did not report any shoulder region symptoms, other than pain. There was no weakness or electromyographic abnormality in the proximal muscles. Ultrasonography revealed focal nerve enlargement in the region 7 cm proximal to the elbow (maximum CSA: 47 mm2). Ultrasonography only indicated median nerve enlargement from the forearm to the upper arm, which involved focal enlargement; no other nerve enlargement (e.g., ulnar and radial nerves) was observed. MRI of the left brachial plexus indicated normal signals. Three months after onset, IVIG was administered but was ineffective. Detailed physical examination after admission revealed indolent swelling of the testes, and a positron emission tomography-computed tomography scan performed during follow-up revealed fluorodeoxyglucose accumulation in the left adrenal gland and bilateral testicles (Fig. 5). Orchiectomy confirmed diffuse, large B-cell lymphoma, and the patient underwent chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]). He subsequently experienced remission and amelioration of the neurologic symptoms in the upper limb, including recovery of muscle strength and decreased sensory impairment.
3.6. Patient summary In all patients, including those who only clinically presented with AIN dysfunction, the electromyogram showed denervation potentials in the median nerve territory (e.g., the pronator teres muscle). Abnormal findings were also observed in the ulnar and radial neural regions in patient 4. No serologic abnormalities were observed in any patients, and all antiganglioside antibody test results were negative. The
Fig. 4. Ultrasonograms of patient 4. A: Cross-sectional scans of the median nerve in the region 5 cm proximal to the elbow (cross-sectional area: 17 mm2). B: A longitudinal scan showing several hourglass-like, incomplete constrictions of a fascicle of the median nerve at the elbow. Lat: lateral, med: median, dis: distal, prox: proximal.
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Fig. 5. A: Ultrasonograms of patient 5 showing nerve enlargement in the region 7 cm proximal to the elbow (maximum cross-sectional area: 47 mm2). B: A longitudinal scan showing constriction of a fascicle of the median nerve at the elbow. Dashed line: nerve epineurium, dotted line: nerve fascicle. C: Positron emission tomogram of patient 5 showing accumulation of 18F-fluoro-2-deoxy-D-glucose in the median nerve at the elbow (arrow), left adrenal gland, and both testicles (circles).
ultrasonograms in all patients demonstrated neural swelling in the median nerve 3–7 cm proximal to the elbow. Hourglass-like constriction of the nerve fascicle was observed in patients 2, 3, and 4. Although the clinical symptoms of patient 5 were not significantly different from those of the other patients, the ultrasonogram showed prominent neural swelling. Impairment of the muscles innervated by the AIN appeared to be caused by compression of malignant lymphoma cells invading the perineurium. In patients 1, 2, and 3, no short-term amelioration of clinical symptoms was noted following IVIG administration, but the clinical
course of patient 2 was more favorable, possibly because treatment was initiated at a comparatively early stage (Table 1). 4. Discussion NA is assumed to have a complex etiology that involves autoimmune, mechanical, and genetic factors. Observations that symptoms are often preceded by an antecedent infection, vaccination, or immunomodulating treatment support the hypothesis of “immune-
Table 1 Patients' clinical characteristics. Patient no., age, and sex
Muscle weakness
Case 1 30 years old Male
PT, FCR, FDP, Median: 18-mm2 CSA on the affected side vs. 9-mm2 FDS, PQ, APB, OP non-affected side in the region 5 cm proximal to the elbow
Case 2 46 years old Male
FDP, FPL, PQ
Median: 20-mm2 CSA on the affected side vs. 9-mm2 non-affected side in the region 3 cm proximal to the elbow Hourglass-like constriction (+)
Case 3 47 years old Female
PT, FCU, FDS, FDP, FPL, PQ
Median: 19-mm2 CSA on the affected side vs. 10-mm2 non-affected side in the region 3 cm proximal to the elbow Hourglass-like constriction (+)
Case 4 58 years old Male
FDP, FDS, FPL, FDI, ADM, EDC
Median: 17-mm2 CSA on the affected side and non-affected side in the region 5 cm proximal to the elbow Hourglass-like constriction (+)
Case 5 46 years old Male
FDP, FPL, PQ
Median: 47-mm2 CSA on the affected side vs. 12-mm2 non-affected side in the region 7 cm proximal to the elbow
Ultrasonographic findings
EMG findings
Clinical course
Median MCS: APB CMAPs, low-voltage amplitude nEMG: APB, PQ, & FCR, active denervation, decreased recruitment, & rapid firing rate Median MCS: APB CMAP, normal amplitude FPL CMAP, low-voltage amplitude nEMG: PT, PQ, & FPL, active denervation & reduced recruitment Median MCS: APB CMAP, normal amplitude FPL CMAP, low-voltage amplitude nEMG: PT, PQ, & FCR, active denervation & reduced recruitment Median MCS: APB CMAP, normal amplitude PQ CMAP, low-voltage amplitude nEMG: FDI, EDC, active denervation, & decreased recruitment Median MCS: conduction block in the arm segments nEMG: FCR, PQ, & APB, active denervation, & reduced recruitment
12 months: IVIG therapy, not effective Neurolysis, slightly improved 4 months: IVIG therapy, improved
6 months: IVIG therapy, not effective Neurolysis, not effective 7 months: Neurolysis, not effective
4 months: chemotherapy (R-CHOP), improved
Abbreviations: PT: pronator teres, PQ: pronator quadratus, FPL: flexor pollicis longus, FDS: flexor digitorum superficialis, FDP: flexor digitorum profundus, FCR: flexor carpi radialis, OP: opponens pollicis, APB: abductor pollicis brevis, EDC: extensor digitorum communis, FDI: first dorsal interosseous, ADM: abductor digiti minimi; CMPAs: compound muscle action potentials, nEMG: normalized electromyography, IVIG, intravenous immunoglobulin, no., number, R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.
Y. Noda et al. / Journal of the Neurological Sciences 377 (2017) 1–5
mediated brachial plexopathy.” To date, most classical NA lesions have been thought to be in the brachial plexus or proximal area. However, NA develops focally as neuritis in the upper limb and is followed by localized amyotrophy after pain diminishes; the subtypes involving AIN palsy or posterior interosseous nerve palsy may also present as distal NA. For this reason, NA is believed to be the cause of AIN palsy. Furthermore, recent reports state that mononeuropathy, such as median or radial nerve palsy, may indicate NA pathology [2,7,8]. In cases of spontaneous anterior or posterior interosseous mononeuropathy, “hourglass-like constrictions” of the nerve fascicle have been widely reported on an ultrasonogram and during intraoperative observation [5,9–12]. There was no sign of prior infection or obvious trauma in our patients, but muscle atrophy had progressed, originating as sudden focal pain in the scapula region. After excluding etiologies, including immune diseases (e.g., chronic inflammatory demyelinating polyneuropathy or multifocal motor neuropathy) and malignant tumors, the ultrasonographic and electromyographic findings indicated proximal median neuropathy. In all patients, including those who only clinically presented with AIN dysfunction, the electromyogram demonstrated denervation potentials in the proximal median nerve territory (e.g., the pronator teres muscle). Abnormal findings were also observed in the ulnar and radial neural regions (e.g., abductor digiti minimi muscle). Based on the aforementioned findings, and medical history and patient examination, we diagnosed all patients as having distal NA, excluding patient 5 who was found to have a malignant tumor. Arányi et al. classified ultrasonographic findings from 14 patients with NA into one of four categories: neural swelling, incomplete hourglass-like constriction of the nerve fascicle, complete hourglass-like constriction of the nerve fascicle (compression), and twisting of the nerve fascicle. They also described individual clinical courses of each category. On the basis of their findings, they hypothesized that NA develops from inflammation-based neural swelling and progresses from incomplete hourglass-like constriction of the nerve fascicle to complete compression, making natural remission difficult [13]. Ultrasonograms in our cohort showed neural swelling in all 5 patients and incomplete hourglass-like constriction of the nerve fascicle in patients 2, 3, and 4 using the aforementioned classification system. Furthermore, even in patients whose clinical symptoms were limited to the muscles innervated by AIN, ultrasonograms showed lesions in the non-branching region of the AIN in the upper arm rather than in the branching region in the forearm [5,10]. Attempts have been made to treat typical NA with immunotherapies, such as steroids and IVIG, but only a few reports have described the effects of immunotherapy on spontaneous neuropathy accompanied by neural swelling. In the present study, clinical courses were only favorable in the patients who received immunotherapy during a comparatively early stage. It is difficult to draw any conclusions about treatment efficacy because of the limited number of subjects; however, there is a possibility that the patients' prognoses improved following immunotherapy [14,15,16]. Collectively, our findings suggest that an immediate detailed examination with ultrasonography and electromyography can facilitate early diagnosis, and it is associated with improved prognoses.
5
In conclusion, ultrasonography can be useful for patients with suspected AIN palsy, as it can locate the abnormality and differentiate it from other diseases. This imaging technique should be widely used when considering treatment options during the early stages of the disease. Conflicts of interest None. Findings This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgment None. References [1] A. Nagano, Spontaneous anterior interosseous nerve palsy, J. Bone Joint Surg. (Br.) 85 (3) (2003) 313–318. [2] J.J. Van Eijk, J.T. Groothuis, N. Van Alfen, Neuralgic amyotrophy: an update on diagnosis, pathophysiology, and treatment, Muscle Nerve 53 (3) (2016) 337–350. [3] Y. Chi, N.G. Harness, Anterior interosseous nerve syndrome, J. Hand. Surg. [Am.] 35 (12) (2010) 2078–2080. [4] K. Ochi, Y. Horiuchi, K. Tazaki, S. Takayama, T. Matsumura, Surgical treatment of spontaneous anterior interosseous nerve palsy: a comparison between minimal incision surgery and wide incision surgery, J. Plast. Surg. Hand Surg. 47 (3) (2013) 213–218. [5] N. van Alfen, Clinical and pathophysiological concepts of neuralgic amyotrophy, Nat. Rev. Neurol. 7 (6) (2011) 315–322. [6] Y. Nakashima, T. Sunagawa, R. Shinomiya, M. Ochi, High-resolution ultrasonographic evaluation of "hourglass-like fascicular constriction" in peripheral nerves: a preliminary report, Ultrasound Med. Biol. 40 (7) (2014) 1718–1721. [7] N. van Alfen, B.G. van Engelen, The clinical spectrum of neuralgic amyotrophy in 246 cases, Brain 129 (Pt 2) (2006) 438–450. [8] A.J. Sumner, Idiopathic brachial neuritis, Neurosurgery 65 (4 Suppl) (2009) A150–A152. [9] Y. Pan, S. Wang, D. Zheng, W. Tian, G. Tian, P.C. Ho, H.S. Cheng, Y. Zhong, Hourglasslike constrictions of peripheral nerve in the upper extremity: a clinical review and pathological study, Neurosurgery 75 (1) (2014) 10–22. [10] H. Yasunaga, T. Shiroishi, K. Ohta, H. Matsunaga, Y. Ota, Fascicular torsion in the median nerve within the distal third of the upper arm: three cases of nontraumatic anterior interosseous nerve palsy, J. Hand. Surg. [Am.] 28 (2) (2003) 206–211. [11] D. Lieba-Samal, S. Jengojan, G. Kasprian, C. Wober, G. Bodner, Neuroimaging of classic neuralgic amyotrophy, Muscle Nerve (2016). [12] Y.W. Pan, S. Wang, G. Tian, C. Li, W. Tian, M. Tian, Typical brachial neuritis (Parsonage-Turner syndrome) with hourglass-like constrictions in the affected nerves, J. Hand. Surg. [Am.] 36 (7) (2011) 1197–1203. [13] Z. Aranyi, A. Csillik, K. Devay, M. Rosero, P. Barsi, J. Bohm, T. Schelle, Ultrasonographic identification of nerve pathology in neuralgic amyotrophy: enlargement, constriction, fascicular entwinement, and torsion, Muscle Nerve 52 (4) (2015) 503–511. [14] J.J. van Eijk, N. van Alfen, M. Berrevoets, G.J. van der Wilt, S. Pillen, B.G. van Engelen, Evaluation of prednisolone treatment in the acute phase of neuralgic amyotrophy: an observational study, J. Neurol. Neurosurg. Psychiatry 80 (10) (2009) 1120–1124. [15] K.S. Naito, K. Fukushima, S. Suzuki, M. Kuwahara, H. Morita, S. Kusunoki, S. Ikeda, Intravenous immunoglobulin (IVIg) with methylprednisolone pulse therapy for motor impairment of neuralgic amyotrophy: clinical observations in 10 cases, Intern. Med. 51 (12) (2012) 1493–1500. [16] K. Ochi, H. Kato, Pathophysiology and treatment of spontaneous anterior interosseous nerve palsy and spontaneous posterior interosseous nerve palsy, Brain Nerve 66 (12) (2014) 1441–1452.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Clinical Short Communication
Ultrasonographic findings of proximal median neuropathy: A case series of suspected distal neuralgic amyotrophy Yoshikatsu Noda a, Kenji Sekiguchi a,⁎, Hideki Tokuoka a, Tetsuya Oda b, Hirotoshi Hamaguchi b, Fumio Kanda a, Tatsushi Toda a a b
Division of Neurology, Kobe University Graduate School of Medicine, Japan Department of Neurology, Kita-HARIMA Medical Center, Japan
a r t i c l e
i n f o
Article history: Received 1 September 2016 Received in revised form 21 March 2017 Accepted 22 March 2017 Available online 24 March 2017 Keywords: Ultrasonography Neuralgic amyotrophy Proximal median neuropathy Anterior interosseous nerve palsy Hourglass-like appearance
a b s t r a c t Spontaneous anterior interosseous nerve (AIN) palsy develops following the resolution of nerve pain, which may be considered as distal neuralgic amyotrophy. NA is assumed to have a complex etiology, but an autoimmune mechanism is likely involved. However, precise assessment of the lesion is challenging. We examined five consecutive patients with suspected spontaneous AIN palsy using ultrasonography. On electromyography, all patients exhibited denervation potentials in the muscles, not only in the AIN territory, but also in the proximal median nerve territory (e.g., the flexor carpi radialis or pronator teres). Ultrasonography of the median nerve demonstrated neural swelling at the proximal side of the medial epicondyle in four patients and an hourglasslike constriction of the nerve fascicle in three patients. Four patients were diagnosed with distal neuralgic amyotrophy; of these, three received intravenous immunoglobulin administration, but only limited beneficial effect was achieved in one patient with early stage disease. One patient showed significant median nerve hypertrophy on ultrasonography and was diagnosed with neurolymphomatosis following the detection of malignant lymphoma during a systemic survey. Our experience demonstrates that ultrasonography for proximal median neuropathy presenting as AIN palsy may be useful for the accurate lesion assessment. © 2017 Elsevier B.V. All rights reserved.
1. Introduction The anterior interosseous nerve (AIN) branches from the median nerve at the elbow and typically innervates the flexor pollicis longus, flexor digitorum profundus (including the index and sometimes the middle fingers), and pronator quadratus muscles. Weakness of these muscles leads to defective flexion of the distal phalanges of the thumb and index finger when the patient is asked to make the “OK” sign; this is known as the “tear drop sign.” Because there are many anatomical variations of the AIN, patients do not always present with typical palsy [1]. Known causes of non-traumatic AIN palsy include space-occupying lesions, compression neuropathy, and pronator teres syndrome; “spontaneous” AIN palsy is considered if medical history, physical examination, and imaging fail to reveal a clear cause. Spontaneous AIN palsy often manifests approximately 1–2 weeks after resolution of idiopathic
Abbreviations: AIN, anterior interosseous nerve; NA, neuralgic amyotrophy; IVIG, intravenous immunoglobulin; CMAPs, compound muscle action potentials; CSA, cross sectional area. ⁎ Corresponding author at: Division of Neurology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chou-ku, Kobe City, Hyogo 650-0017, Japan. E-mail address: [email protected] (K. Sekiguchi).
http://dx.doi.org/10.1016/j.jns.2017.03.037 0022-510X/© 2017 Elsevier B.V. All rights reserved.
nerve pain in the affected limb, which is a distal subtype of neuralgic amyotrophy (NA) [2]. NA is assumed to have a complex etiology involving autoimmune, mechanical, and genetic factors. Observations that symptoms are often preceded by an antecedent infection, vaccination, or immunomodulating treatment support the hypothesis that attacks are immunomediated, explaining the term “immune-mediated brachial plexopathy” preferred by some, but no clear pathological mechanism has been identified [3]. Given the many uncertainties surrounding AIN palsy, there is no current consensus on an appropriate therapeutic protocol. Neurolysis has been reported as an effective treatment option, and given the potential involvement of inflammatory processes, immunotherapies such as corticosteroids or intravenous immunoglobulin (IVIG) are often administered [4,5]. In recent years, ultrasonography has been described as useful for diagnosing peripheral neuropathy. To further investigate these possible treatment modalities, we evaluated ultrasonographic findings of the peripheral nerve and clinical courses of patients with AIN palsy [6]. 2. Methods The subjects in this study were referred to our department between 2013 and 2015 for suspected spontaneous AIN palsy. We included five patients experiencing idiopathic focal pain in an upper limb and
2
Y. Noda et al. / Journal of the Neurological Sciences 377 (2017) 1–5
Fig. 1. Ultrasonograms of patient 1 showing side-to-side comparisons of the median nerve (circled). A: The 9-mm2 non-affected side (right arm) vs. B: cross-sectional area of the 18-mm2 affected side (left arm), in the region 5 cm proximal to the elbow. Lat: lateral, med: median.
subsequently decreased muscle strength in the fingers of the same limb (predominantly the flexor muscles of the thumb and index finger). The diagnosis was based on medical history, clinical examination, and ancillary investigations, such as magnetic resonance imaging of the cervical spine or lumbar puncture, to exclude other causes. All patients provided informed consent. Ultrasonography was performed using an APLIO™ 500 (Toshiba Medical Systems), a prosound α10 (Hitachi-Aloka Medical), and a 12–18 MHz linear probe. We identified the main trunk of the median nerve (including the branch of the AIN with the proximal part from the elbow) from the forearm to the upper arm region, and searched for the characteristic findings: neural swelling or hourglasslike constriction of the nerve branch. When the probe is lowered to the distal part of the constricted branch, it separates from the trunk of the median nerve in the pronator teres muscle and branches as the anterior interosseous nerve. To study nerve conduction, we applied surface electrodes to the abductor pollicis brevis, pronator quadratus, and flexor hallucis longus muscles. We then applied a supramaximal stimulus to the wrist and elbow regions of the median nerve and compared the bilateral compound muscle action potentials (CMAPs). The study met the guidelines of the Ethics Committee of Kobe University and was performed after informed consent was obtained. 3. Results 3.1. Patient 1 A 30-year-old man presented with pain extending from the left shoulder to the fingertips. Clinical examination revealed distal muscle
weakness and atrophy (pronator teres, pronator quadratus, flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, opponens pollicis, and abductor pollicis brevis). He did not report any shoulder region symptoms other than pain. There was no weakness or electromyographic abnormality in the proximal muscles (e.g., anterior serratus and supraspinatus muscles). Ultrasonography revealed neural swelling 5 cm proximal to the elbow (maximum cross sectional area [CSA]: 18 mm2; healthy side: 9 mm2), but there were no signs indicating hourglass-like constriction of the nerve fascicle (Fig. 1). Magnetic resonance imaging (MRI) of the left brachial plexus indicated normal signals. IVIG was administered 12 months after onset but had no effect. Subsequent neurolysis was somewhat effective in decreasing the patient's clinical symptoms.
3.2. Patient 2 A 46-year-old man presented with left shoulder pain. Clinical examination revealed distal muscle weakness (pronator quadratus, flexor digitorum profundus, and flexor pollicis longus). He did not report any shoulder region symptoms besides pain. There was no weakness or electromyographic abnormality in the proximal muscles. Ultrasonography revealed neural swelling 3 cm proximal to the elbow (maximum CSA: 20 mm2; healthy side: 9 mm2), and we suspected hourglass-like constriction of the nerve fascicle (Fig. 2). MRI of the left brachial plexus indicated normal signals. IVIG was administered 5 months after disease onset, and slight recovery of strength was observed in the flexor pollicis longus muscle 2 weeks later. Further gradual improvement of muscle
Fig. 2. Ultrasonograms of patient 2. A: Cross-sectional scans of the median nerve in the region 3 cm proximal to the elbow (cross-sectional area: 20 mm2). B: A longitudinal scan showing constriction of a fascicle of the median nerve at the elbow. Nerves with hourglass-like, incomplete constrictions and enlargements are shown. Dashed line: nerve epineurium, dotted line: nerve fascicle, arrowhead: hourglass-like constrictions, lat: lateral, med: median, dis: distal, prox: proximal.
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Fig. 3. Ultrasonograms of patient 3. A: Cross-sectional scans of the median nerve in the region 3 cm proximal to the elbow (cross-sectional area: 19 mm2). B: A longitudinal scan showing constriction of a fascicle of the median nerve at the elbow. Nerves with hourglass-like incomplete constrictions and enlargements are shown. Dashed line: nerve epineurium, dotted line: nerve fascicle, arrowhead: hourglass-like constrictions, lat: lateral, med: median, dis: distal, prox: proximal.
strength was observed, and complete remission was noted 7 months after disease onset. 3.3. Patient 3 A 47-year-old woman presented with left shoulder pain. Clinical examination revealed distal muscle weakness (pronator teres, pronator quadratus, flexor pollicis longus, flexor digitorum superficialis, flexor digitorum profundus, and flexor carpi radialis). She did not report any shoulder region symptoms other than pain. There was no weakness or electromyographic abnormality in the proximal muscles. Ultrasonography revealed neural swelling in the region 3 cm proximal to the elbow (maximum CSA: 19 mm2; healthy side: 10 mm2), and we suspected hourglass-like constriction of the nerve fascicle in this region (Fig. 3). MRI of the left brachial plexus indicated normal signals. IVIG was administered 7 months after onset, followed by neurolysis, but her symptoms did not improve. 3.4. Patient 4 A 58-year-old man presented with pain in the medial scapular region of the left shoulder. Clinical examination revealed distal muscle weakness (flexor pollicis longus, flexor digitorum superficialis, flexor digitorum profundus, extensor digitorum communis, first dorsal interosseous, and abductor digiti minimi). He did not report any shoulder region symptoms other than pain. There was no weakness or electromyographic abnormality in the proximal muscles. Ultrasonography revealed an hourglass-like constriction of the nerve fascicle 5 cm proximal to the elbow, and mild neural swelling was noted (maximum CSA: 17 mm2) (Fig. 4). MRI of the left brachial plexus indicated normal signals. Neurolysis was performed 6 months after onset, but the patient's symptoms did not improve.
3.5. Patient 5 A 46-year-old man presented with left middle finger pain. Clinical examination revealed distal muscle weakness (pronator quadratus, flexor digitorum profundus, and flexor pollicis longus). He did not report any shoulder region symptoms, other than pain. There was no weakness or electromyographic abnormality in the proximal muscles. Ultrasonography revealed focal nerve enlargement in the region 7 cm proximal to the elbow (maximum CSA: 47 mm2). Ultrasonography only indicated median nerve enlargement from the forearm to the upper arm, which involved focal enlargement; no other nerve enlargement (e.g., ulnar and radial nerves) was observed. MRI of the left brachial plexus indicated normal signals. Three months after onset, IVIG was administered but was ineffective. Detailed physical examination after admission revealed indolent swelling of the testes, and a positron emission tomography-computed tomography scan performed during follow-up revealed fluorodeoxyglucose accumulation in the left adrenal gland and bilateral testicles (Fig. 5). Orchiectomy confirmed diffuse, large B-cell lymphoma, and the patient underwent chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]). He subsequently experienced remission and amelioration of the neurologic symptoms in the upper limb, including recovery of muscle strength and decreased sensory impairment.
3.6. Patient summary In all patients, including those who only clinically presented with AIN dysfunction, the electromyogram showed denervation potentials in the median nerve territory (e.g., the pronator teres muscle). Abnormal findings were also observed in the ulnar and radial neural regions in patient 4. No serologic abnormalities were observed in any patients, and all antiganglioside antibody test results were negative. The
Fig. 4. Ultrasonograms of patient 4. A: Cross-sectional scans of the median nerve in the region 5 cm proximal to the elbow (cross-sectional area: 17 mm2). B: A longitudinal scan showing several hourglass-like, incomplete constrictions of a fascicle of the median nerve at the elbow. Lat: lateral, med: median, dis: distal, prox: proximal.
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Fig. 5. A: Ultrasonograms of patient 5 showing nerve enlargement in the region 7 cm proximal to the elbow (maximum cross-sectional area: 47 mm2). B: A longitudinal scan showing constriction of a fascicle of the median nerve at the elbow. Dashed line: nerve epineurium, dotted line: nerve fascicle. C: Positron emission tomogram of patient 5 showing accumulation of 18F-fluoro-2-deoxy-D-glucose in the median nerve at the elbow (arrow), left adrenal gland, and both testicles (circles).
ultrasonograms in all patients demonstrated neural swelling in the median nerve 3–7 cm proximal to the elbow. Hourglass-like constriction of the nerve fascicle was observed in patients 2, 3, and 4. Although the clinical symptoms of patient 5 were not significantly different from those of the other patients, the ultrasonogram showed prominent neural swelling. Impairment of the muscles innervated by the AIN appeared to be caused by compression of malignant lymphoma cells invading the perineurium. In patients 1, 2, and 3, no short-term amelioration of clinical symptoms was noted following IVIG administration, but the clinical
course of patient 2 was more favorable, possibly because treatment was initiated at a comparatively early stage (Table 1). 4. Discussion NA is assumed to have a complex etiology that involves autoimmune, mechanical, and genetic factors. Observations that symptoms are often preceded by an antecedent infection, vaccination, or immunomodulating treatment support the hypothesis of “immune-
Table 1 Patients' clinical characteristics. Patient no., age, and sex
Muscle weakness
Case 1 30 years old Male
PT, FCR, FDP, Median: 18-mm2 CSA on the affected side vs. 9-mm2 FDS, PQ, APB, OP non-affected side in the region 5 cm proximal to the elbow
Case 2 46 years old Male
FDP, FPL, PQ
Median: 20-mm2 CSA on the affected side vs. 9-mm2 non-affected side in the region 3 cm proximal to the elbow Hourglass-like constriction (+)
Case 3 47 years old Female
PT, FCU, FDS, FDP, FPL, PQ
Median: 19-mm2 CSA on the affected side vs. 10-mm2 non-affected side in the region 3 cm proximal to the elbow Hourglass-like constriction (+)
Case 4 58 years old Male
FDP, FDS, FPL, FDI, ADM, EDC
Median: 17-mm2 CSA on the affected side and non-affected side in the region 5 cm proximal to the elbow Hourglass-like constriction (+)
Case 5 46 years old Male
FDP, FPL, PQ
Median: 47-mm2 CSA on the affected side vs. 12-mm2 non-affected side in the region 7 cm proximal to the elbow
Ultrasonographic findings
EMG findings
Clinical course
Median MCS: APB CMAPs, low-voltage amplitude nEMG: APB, PQ, & FCR, active denervation, decreased recruitment, & rapid firing rate Median MCS: APB CMAP, normal amplitude FPL CMAP, low-voltage amplitude nEMG: PT, PQ, & FPL, active denervation & reduced recruitment Median MCS: APB CMAP, normal amplitude FPL CMAP, low-voltage amplitude nEMG: PT, PQ, & FCR, active denervation & reduced recruitment Median MCS: APB CMAP, normal amplitude PQ CMAP, low-voltage amplitude nEMG: FDI, EDC, active denervation, & decreased recruitment Median MCS: conduction block in the arm segments nEMG: FCR, PQ, & APB, active denervation, & reduced recruitment
12 months: IVIG therapy, not effective Neurolysis, slightly improved 4 months: IVIG therapy, improved
6 months: IVIG therapy, not effective Neurolysis, not effective 7 months: Neurolysis, not effective
4 months: chemotherapy (R-CHOP), improved
Abbreviations: PT: pronator teres, PQ: pronator quadratus, FPL: flexor pollicis longus, FDS: flexor digitorum superficialis, FDP: flexor digitorum profundus, FCR: flexor carpi radialis, OP: opponens pollicis, APB: abductor pollicis brevis, EDC: extensor digitorum communis, FDI: first dorsal interosseous, ADM: abductor digiti minimi; CMPAs: compound muscle action potentials, nEMG: normalized electromyography, IVIG, intravenous immunoglobulin, no., number, R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.
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mediated brachial plexopathy.” To date, most classical NA lesions have been thought to be in the brachial plexus or proximal area. However, NA develops focally as neuritis in the upper limb and is followed by localized amyotrophy after pain diminishes; the subtypes involving AIN palsy or posterior interosseous nerve palsy may also present as distal NA. For this reason, NA is believed to be the cause of AIN palsy. Furthermore, recent reports state that mononeuropathy, such as median or radial nerve palsy, may indicate NA pathology [2,7,8]. In cases of spontaneous anterior or posterior interosseous mononeuropathy, “hourglass-like constrictions” of the nerve fascicle have been widely reported on an ultrasonogram and during intraoperative observation [5,9–12]. There was no sign of prior infection or obvious trauma in our patients, but muscle atrophy had progressed, originating as sudden focal pain in the scapula region. After excluding etiologies, including immune diseases (e.g., chronic inflammatory demyelinating polyneuropathy or multifocal motor neuropathy) and malignant tumors, the ultrasonographic and electromyographic findings indicated proximal median neuropathy. In all patients, including those who only clinically presented with AIN dysfunction, the electromyogram demonstrated denervation potentials in the proximal median nerve territory (e.g., the pronator teres muscle). Abnormal findings were also observed in the ulnar and radial neural regions (e.g., abductor digiti minimi muscle). Based on the aforementioned findings, and medical history and patient examination, we diagnosed all patients as having distal NA, excluding patient 5 who was found to have a malignant tumor. Arányi et al. classified ultrasonographic findings from 14 patients with NA into one of four categories: neural swelling, incomplete hourglass-like constriction of the nerve fascicle, complete hourglass-like constriction of the nerve fascicle (compression), and twisting of the nerve fascicle. They also described individual clinical courses of each category. On the basis of their findings, they hypothesized that NA develops from inflammation-based neural swelling and progresses from incomplete hourglass-like constriction of the nerve fascicle to complete compression, making natural remission difficult [13]. Ultrasonograms in our cohort showed neural swelling in all 5 patients and incomplete hourglass-like constriction of the nerve fascicle in patients 2, 3, and 4 using the aforementioned classification system. Furthermore, even in patients whose clinical symptoms were limited to the muscles innervated by AIN, ultrasonograms showed lesions in the non-branching region of the AIN in the upper arm rather than in the branching region in the forearm [5,10]. Attempts have been made to treat typical NA with immunotherapies, such as steroids and IVIG, but only a few reports have described the effects of immunotherapy on spontaneous neuropathy accompanied by neural swelling. In the present study, clinical courses were only favorable in the patients who received immunotherapy during a comparatively early stage. It is difficult to draw any conclusions about treatment efficacy because of the limited number of subjects; however, there is a possibility that the patients' prognoses improved following immunotherapy [14,15,16]. Collectively, our findings suggest that an immediate detailed examination with ultrasonography and electromyography can facilitate early diagnosis, and it is associated with improved prognoses.
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In conclusion, ultrasonography can be useful for patients with suspected AIN palsy, as it can locate the abnormality and differentiate it from other diseases. This imaging technique should be widely used when considering treatment options during the early stages of the disease. Conflicts of interest None. Findings This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgment None. References [1] A. Nagano, Spontaneous anterior interosseous nerve palsy, J. Bone Joint Surg. (Br.) 85 (3) (2003) 313–318. [2] J.J. Van Eijk, J.T. Groothuis, N. Van Alfen, Neuralgic amyotrophy: an update on diagnosis, pathophysiology, and treatment, Muscle Nerve 53 (3) (2016) 337–350. [3] Y. Chi, N.G. Harness, Anterior interosseous nerve syndrome, J. Hand. Surg. [Am.] 35 (12) (2010) 2078–2080. [4] K. Ochi, Y. Horiuchi, K. Tazaki, S. Takayama, T. Matsumura, Surgical treatment of spontaneous anterior interosseous nerve palsy: a comparison between minimal incision surgery and wide incision surgery, J. Plast. Surg. Hand Surg. 47 (3) (2013) 213–218. [5] N. van Alfen, Clinical and pathophysiological concepts of neuralgic amyotrophy, Nat. Rev. Neurol. 7 (6) (2011) 315–322. [6] Y. Nakashima, T. Sunagawa, R. Shinomiya, M. Ochi, High-resolution ultrasonographic evaluation of "hourglass-like fascicular constriction" in peripheral nerves: a preliminary report, Ultrasound Med. Biol. 40 (7) (2014) 1718–1721. [7] N. van Alfen, B.G. van Engelen, The clinical spectrum of neuralgic amyotrophy in 246 cases, Brain 129 (Pt 2) (2006) 438–450. [8] A.J. Sumner, Idiopathic brachial neuritis, Neurosurgery 65 (4 Suppl) (2009) A150–A152. [9] Y. Pan, S. Wang, D. Zheng, W. Tian, G. Tian, P.C. Ho, H.S. Cheng, Y. Zhong, Hourglasslike constrictions of peripheral nerve in the upper extremity: a clinical review and pathological study, Neurosurgery 75 (1) (2014) 10–22. [10] H. Yasunaga, T. Shiroishi, K. Ohta, H. Matsunaga, Y. Ota, Fascicular torsion in the median nerve within the distal third of the upper arm: three cases of nontraumatic anterior interosseous nerve palsy, J. Hand. Surg. [Am.] 28 (2) (2003) 206–211. [11] D. Lieba-Samal, S. Jengojan, G. Kasprian, C. Wober, G. Bodner, Neuroimaging of classic neuralgic amyotrophy, Muscle Nerve (2016). [12] Y.W. Pan, S. Wang, G. Tian, C. Li, W. Tian, M. Tian, Typical brachial neuritis (Parsonage-Turner syndrome) with hourglass-like constrictions in the affected nerves, J. Hand. Surg. [Am.] 36 (7) (2011) 1197–1203. [13] Z. Aranyi, A. Csillik, K. Devay, M. Rosero, P. Barsi, J. Bohm, T. Schelle, Ultrasonographic identification of nerve pathology in neuralgic amyotrophy: enlargement, constriction, fascicular entwinement, and torsion, Muscle Nerve 52 (4) (2015) 503–511. [14] J.J. van Eijk, N. van Alfen, M. Berrevoets, G.J. van der Wilt, S. Pillen, B.G. van Engelen, Evaluation of prednisolone treatment in the acute phase of neuralgic amyotrophy: an observational study, J. Neurol. Neurosurg. Psychiatry 80 (10) (2009) 1120–1124. [15] K.S. Naito, K. Fukushima, S. Suzuki, M. Kuwahara, H. Morita, S. Kusunoki, S. Ikeda, Intravenous immunoglobulin (IVIg) with methylprednisolone pulse therapy for motor impairment of neuralgic amyotrophy: clinical observations in 10 cases, Intern. Med. 51 (12) (2012) 1493–1500. [16] K. Ochi, H. Kato, Pathophysiology and treatment of spontaneous anterior interosseous nerve palsy and spontaneous posterior interosseous nerve palsy, Brain Nerve 66 (12) (2014) 1441–1452.