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Diabetic Cranio-Cervico-Radiculoplexus Neuropathy
PM R 7 (2015) 1189-1193
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Case Presentation
Diabetic Cranio-Cervico-Radiculoplexus Neuropathy Gaurav Gupta, MD, FRCPC, Rami Massie, MD, FRCPC, Timothy J. Doherty, MD, PhD, FRCPC, P.R. Bourque, MD, FRCPC, Mohan Radhakrishna, MD, FRCPC, Roderick J. Finlayson, MD, FRCPC, Markus Besemann, MD, FRCPC, LTC, Emmanuel Simantirakis, MD, FRCPC, P. James Bonham Dyck, MD
Abstract We describe a case of a 53-year-old man with type 2 diabetes mellitus in whom cervical-radiculoplexus neuropathy developed, with concomitant cranial and phrenic nerve involvement, occurring as a stepwise, monophasic course. The patient had a presumed remote history of idiopathic cervical-radiculoplexus neuropathy.
Introduction Recent reports suggest that diabetic cervicalradiculoplexus neuropathy (DCRPN) is a distinct entity when compared with idiopathic CRPN [1]. Radiculoplexus neuropathy (RPN) is likely an immunemediated microvasculitis resulting in ischemic axonal damage. It can affect patients with or without diabetes and can manifest at the cervical level (ie, CRPN), thoracic level (ie, thoracic radiculoneuropathy), and lumbar level (ie, lumbosacral radiculoplexus neuropathy [LRPN]) [2-4]. Case Description A 53-year-old man with right hand dominance presented with a 1-month history of right upper extremity pain and paresthesias. His medical history included type 2 diabetes mellitus (DM) with no known microvascular complications, previous right “viral” upper trunk brachial plexopathy at age 19 years with full functional and neurologic recovery, dyslipidemia, pigmented villonodular synovitis, and shoulder dislocation. Medications included rosuvastatin and metformin. He had no family history of brachial plexopathy. The patient described severe right posterolateral arm pain and paresthesias involving digits 1-3, followed by
weakness in the right triceps 1 week later. A physical examination completed 6 weeks after the onset of symptoms showed severe weakness of the triceps (Medical Research Council [MRC] grade 2/5), with mild weakness of the deltoid, supraspinatus, infraspinatus, flexor carpi radialis, and pronator teres (MRC grade 4þ/5). This weakness was accompanied with a decrease in the right triceps reflex and impaired sensation over the dorsal aspect of the arm and thumb. At 3 months from symptom onset, he had much less right upper arm pain, but his triceps strength had decreased. New-onset forearm and hand pain/allodynia also developed, along with severe hand intrinsic weakness. His physical examination at this time showed sensory abnormalities in the lateral aspect of the forearm and the entire hand, along with weakness of triceps (0/5), extensor carpi ulnaris (1/5), pronator teres (3/5), abductor pollicis brevis (3/5), flexor digitorum longus (median fibers) (0/5), flexor pollicis longus (0/5), flexor carpi radialis (0/5), and first dorsal interosseous (3/5). He also had mild weakness of the biceps (4/5), extensor carpi radialis (4e/5) and supinator (4/5), along with a decreased right triceps and quadriceps reflex. At 5-month follow-up, the patient reported improved upper arm pain and triceps weakness (MRC grade 1/5) but a 20-lb weight loss and ongoing hand pain and weakness. At 6 months after the onset of symptoms,
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diplopia developed that was worse with distance, with mild restriction of right eye abduction, which persisted for approximately 1 week and then resolved. At 1 year and 4 months after symptom onset, he had minor distal hand pain and improved triceps strength (3/5), with ongoing moderate hand weakness. At no point did he experience any autonomic symptoms. Relevant blood work to rule out a metabolic, infectious, and inflammatory condition was negative. Hemoglobin A1C performed 2 years prior to onset of symptoms was 0.063 (normal, 0.048-0.060). A chest radiograph showed right hemidiaphragm elevation and left Zung scarring/atelectasis. Magnetic resonance imaging (MRI) scans of the cervical spine, brachial plexus, and brain (with and without contrast enhancement) and shoulder (without contrast enhancement) were normal. A positron emission tomography scan was negative. These procedures were all performed within the first 6 months of the patient’s initial presentation. The patient refused to undergo a lumbar puncture to evaluate his cerebrospinal fluid. Electrodiagnostic tests are reported in Table 1. Genetic testing for peripheral myelin protein 22 (PMP-22) deletion or septin 9 apoprotein (SEPT9) mutation was not performed. Treatment focused on pain control using neuropathic pain medications (gabapentin, nortriptyline, and naproxen) and opioids (oxycodone, immediate and controlled release). The patient refused treatment with intravenous high-dose methylprednisolone. Discussion RPN was first described in 1890 by Bruns but has been known by other names over the years, including diabetic myelopathy, diabetic amyotrophy, diabetic polyradiculopathy, femoral and femoral-sciatic neuropathy of diabetes, proximal diabetic neuropathy, diabetic lumbosacral plexopathy, Bruns-Garland syndrome, diabetic motor or paralytic neuropathy, and diabetic mononeuritis multiplex [1,3]. Nomenclature inconsistency is mirrored by the variability in clinical presentation included in the spectrum of this condition, with some authors describing proximal limb involvement and others discussing multifocal, widespread presentations involving distal regions or a focal/unilateral condition progressing to a more widespread distal process [3,4]. Differential Diagnosis Various types of neuropathies related to diabetes have been described. These neuropathies can be subdivided according to pathophysiology: metabolic-microvascularhypoxic (eg, polyneuropathy and autonomic neuropathy), inflammatory/immune (eg, RPN, thoracic radiculoneuropathy, and diabetic cachexia), compressive (eg, median, ulnar, and/or peroneal mononeuropathies), complication-related (eg, neuropathy of ketoacidosis,
neuropathy of chronic renal failure, neuropathy with large vessel ischemia, and hypoglycemic neuropathy) and treatment-related (eg, insulin neuritis and hyperinsulin neuropathy) [5,6]. In diabetic or nondiabetic patients, peripheral neuropathic cause of unilateral upper limb pain, weakness, and sensory changes include idiopathic neuralgic amyotrophy (INA; eg, Parsonage-Turner syndrome), compressive and infiltrative brachial plexopathies, hereditary neuralgic amyotrophy (HNA), and neurogenic thoracic outlet syndrome [7]. In this case, a differential diagnosis of INA and HNA should be considered. Both conditions have been reported to occur in a stepwise and/or polyphasic course and have involvement of nerves outside of the brachial plexus. Based on their results, van Alfen and van Engelen [8] advocate that INA be considered a “mononeuropathia multiplex” with preferential involvement of specific regions. It is also likely that the underlying cause is immune, and therefore it follows that CRPN and INA refer to the same clinical entity. CRPN offers a more accurate clinical description than “amyotrophy,” “Parsonage-Turner syndrome” or “neuritis” [8]. Although INA/CRPN has been described to occur in both a stepwise and polyphasic course, to our knowledge, hereditary neuralgic amyotrophy has not been specifically associated with a stepwise presentation or weight loss [8]. The lack of a family history, although not excluding HNA, also makes it less likely. Specific genetic testing may have helped to alleviate further diagnostic confusion. It was not performed because it was not readily available at the time and would not have appreciably changed our management in this case. Should this patient have a recurrence, we can consider genetic testing at that time. Epidemiology RNP can occur in a small percentage of diabetic patients but is also described in nondiabetic patients [3,4]. It can affect patients between 36 and 76 years of age, with the average being 65 years [3,4]. RPN is more common in patients with type 2 DM compared with patients with type 1 DM. When compared with patients who have diabetic polyneuropathy, patients with diabetic RPN tends to have better controlled diabetes, short duration of diabetic disease (eg, median time to onset of 4 years), and possibly even be diagnosed with diabetes after RPN presentation. Patients have lower associated body mass index and a lower likelihood of insulin utilization and systemic complications (ie, nephropathy, retinopathy, and cardiovascular disease) [3,4]. Symptomatology Patients often present with acute or subacute severe, asymmetric, limb, or thoracic pain and paresthesias
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Table 1 Electrodiagnostic studies Region
1 Month After Symptom Onset
3 Months After Symptom Onset
4 Months After Symptom Onset
Median
NCS Mild decreased CMAP
NCS Normal CMAP EMG Acute (new) pronator teres (PSW, FP, RR)
NCS Severe decreased CMAP and forearm conduction block Absent SNAP digit 3 EMG Acute denervation FPL, FCR (PSW, FP, RR)
Radial
NCS Decreased CMAP and proximal block SNAP normal EMG Acute denervation triceps (PSW, FP, RR)
NCS Decreased SNAP 50% Decreased CMAP 70%
EMG Acute denervation EI, triceps (PSW, FP, RR)
Axillary
EMG Deltoid denervation (PSW, polyphasia)
Ulnar
EMG Deltoid PSW, CRD, and CD NCS Decreased CMAP
NCS Further decrease CMAP SNAP decrease 40% EMG Acute denervation FDI (PSW, FP, RR)
Miscellaneous
NCS Decreased right SNAP-MAC EMG Right C7 denervation PS (PSW, FP)
NCS Decreased radial CMAP for ERB stimulation EMG Right C7 denervation PS (PSW, FP)
NCS Right peroneal normal EMG Normal thoracic and lumbar PS
Conclusion/differential diagnosis
Right C7 radiculopathy vs middle trunk plexopathy CTS Chronic upper trunk plexopathy
Middle trunk plexopathy Diabetes-related paraspinal denervation ? Ulnar neuropathy at elbow
Diabetic craniocervical-radiculoplexus neuropathy
NCS ¼ nerve conduction studies; CMAP ¼ compound motor action potential; EMG ¼ electromyography; PSW ¼ positive sharp waves; FP ¼ fibrillation potentials; RR ¼ reduced recruitment; SNAP ¼ sensory nerve action potential; FPL ¼ flexor pollicis longus; FCR ¼ flexor carpi radialis; EI ¼ extensor indices proprius; MU ¼ motor unit; CD ¼ chronic denervation (large amplitude, long duration, polyphasic units, reduced recruitment); CRD ¼ complex repetitive discharge; FDI ¼ first dorsal interosseous; MAC ¼ medial antebrachial cutaneous; C7 ¼ 7th cervical nerve root; ERB ¼ extensor carpi radialis brevis; PS ¼ paraspinal; CTS ¼ carpal tunnel syndrome.
followed by weakness that evolves over weeks to months. The course has been defined as monophasic when neurologic symptoms/signs occur within 1 year of symptom onset [1,3,4]. As in this case, up to 21% of patients can have a stepwise course within the same year, and another 21% have been described as having recurrent symptoms and/or signs after more than 1 year of clinical stability (ie, a polyphasic course) [1]. In the case of our patient, this current episode could represent a recurrence of his previously described “viral upper trunk plexopathy” that he experienced at age 19 years. In the current episode, although he had stepwise-type worsening of symptoms at 3 and 6 months after presentation, the entire episode lasted less than 1 year. Until recently, most studies reported cervical/upper limb involvement primarily in association with co-existing lumbar/lower limb involvement [1]. In persons with LRPN, sensory and motor loss commonly occurs in a femoral/ obturator greater than sciatic nerve distribution, usually
beginning proximally, and then spreading distally and/or contralaterally. Associated symptoms can include weight loss of more than 10 lb, back pain, and autonomic dysfunction in up to 50% of patients [1,4]. Compared with persons who have diabetic LRPN, persons who have DCRPN present in a similar fashion, with very severe pain followed by disabling weakness and associated autonomic symptoms and weight loss. Small differences include more frequent weakness and/or reports of sensory symptoms at onset, more frequent associated phrenic or cranial neuropathies, and less frequent weight loss and bilateral spread in persons with DCRPN [1]. In one DCRPN cohort, more than 50% of patients had involvement outside the brachial plexus, and particularly relevant to our case, the phrenic nerve was involved in 5 of 80 patients and cranial nerves were involved in 2 of 80 patients [1]. Based on this same recent work, compared with persons with idiopathic CRPN, patients with DCRPN more frequently have
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associated weight loss, autonomic features, bilateral disease, and lower trunk and diffuse regional involvement [1]. This phenotypic difference, along with the much higher co-occurrence of thoracic RPN and LRPN, form the basis for considering DCRPN as a distinct clinical entity from CRPN. Diagnostic Studies Nerve conduction studies are characterized by an axonal loss pattern with reduction of compound motor amplitudes, sensory amplitudes, and slowing consistent with an axonal process. Electromyographic findings show neuropathic changes found in an asymmetric, multifocal pattern, which includes multiple myotomes, paraspinal muscles, and regions that may not be clinically affected. Autonomic and quantitative sensory testing can be abnormal, but is not necessarily diagnostic [3,4]. Laboratory abnormalities can include an elevated erythrocyte sedimentation rate, rheumatoid factor, antinuclear antibodies, and cerebrospinal fluid protein without pleocytosis. Nerve roots and plexus enhancement can be seen on MRI, but imaging studies are most useful in ruling out compressive pathologic conditions (eg, tumor, hematoma, and compressive polyradiculopathy) [3,4]. MRI findings in the CRPN can show increased T2 signal, contrast enhancement, and nerve hypertrophy [1]. Pathophysiology/Histology All nerve subtypes can be involved (ie, motor, sensory, and autonomic), and histologic findings of cutaneous sensory nerves are consistent with neural and vascular changes. The pattern of elevated inflammatory mediators (eg, neural factor kappa beta, intercellular adhesion moleculee1, tumor necrosis factorea, and interleukin 6) and, most importantly, the pathologic changes seen on nerve biopsies are suggestive of a small-vessel microvasculitis isolated to the peripheral nerves, but the exact cause has been extensively debated in the literature [3-5]. Treatment In uncontrolled trials, medication trials have included prednisone or intravenous immunoglobulin alone or in combination with other immunosuppressants (eg, azathioprine and cyclophosphamide), plasmapheresis, and intravenous methylprednisolone, with patients generally showing improvements in pain, weakness, and/or function [3,4]. In a double-blind, randomized, controlled trial, intravenous methylprednisolone, when compared with placebo, improved neuropathic pain and provided lower limb neurologic recovery 30 days sooner. It was also suggested that initiation of treatment within 3 months may lead to better outcomes overall [9].
Supportive treatment is important in the management of these conditions, including analgesics, physical therapy, education, home safety assessments, bracing, personal care, and mobility aids [3,4]. Outcomes Most patients achieve spontaneous partial recovery even without treatment by 18 months. Pain generally subsides within weeks to a few months, followed by a slow, gradual improvement in motor function. The motor recovery is usually incomplete, especially for distal weakness, and may have a variable impact on function [4]. As described here, up to one fifth of patients can have a multiphasic course, whereas another one fifth of patients can have recurrent episodes of pain and weakness after a year of clinical stability [1,3,4]. Conclusion CRPN is an immune-mediated vasculitis that can occur in diabetic and nondiabetic patients. The patient in this case had a stepwise, monophasic illness that included involvement of his cervical plexus and cranial nerves. Investigations were noncontributory and treatment was conservative, leading to partial distal motor recovery. Although a genetic cause could not be formally excluded, especially given his previous episode at age 19 years, the stepwise course within the same year, involvement of other body regions (phrenic and cranial neuropathies), associated weight loss, and associated DM favor the diagnosis of DCRPN. References 1. Massie R, Mauermann ML, Staff NP, et al. Diabetic cervical radiculoplexus neuropathy: A distinct syndrome expanding the spectrum of diabetic radiculoplexus neuropathies. Brain 2012;135: 3074-3088. 2. Dyck PJ, Norell JE, Dyck PJ. Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus neuropathy. Neurology 1999;53: 2113-2121. 3. Dyck PJ, Windebank AJ. Diabetic and nondiabetic lumbosacral radiculoplexus neuropathies: New insights into pathophysiology and treatment. Muscle Nerve 2002;25:477-491. 4. Bhanushali MJ, Muley SA. Diabetic and non-diabetic lumbosacral radiculoplexus neuropathy. Neurol India 2008;56:420-425. 5. Tracy JA, Dyck PJ. The spectrum of diabetic neuropathies. Phys Med Rehabil Clin N Am 2008;19:1-26. 6. Sinnreich M, Taylor BV, Dyck PJ. Diabetic neuropathies. Classification, clinical features, and pathophysiological basis. Neurologist 2005;11:63-79. 7. Khadilkar SV, Khade SS. Brachial plexopathy. Ann Indian Acad Neurol 2013;16:12-18. 8. van Alfen N, van Engelen BG. The clinical spectrum of neuralgic amyotrophy in 246 cases. Brain 2006;129:438-450. 9. Dyck PJ, Bosch PE, Grant I, et al. The multi-center double-blind controlled trial of IV methylprednisolone in diabetic lumbosacral radiculoplexus neuropathy. Neurology 2006;66(Suppl 2):A191.
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Disclosure G.G. Department of Medicine, McGill University, Montreal, Quebec, Canada; Department of National Defence, Canadian Forces Health Centre, Ottawa, Ontario, Canada; Alan Edwards Pain Management Unit, Montreal General Hospital, 1650 Ave Cedar, Montreal, Quebec, Canada H3G-1A4. Address correspondence to: G.G.; e-mail: [email protected] Disclosures outside this publication: grants/grants pending, Ultrasound Study (money to institution); payment for lectures including service on speakers bureaus, speaking honorariums for conferences (money to author) R.M. Department of Neurology, University of Montreal, Montreal, Quebec, Canada Disclosures outside this publication: payment for lectures including service on speakers bureaus, multiple lectures paid for by different drug companies (money to author); royalties, Author for UpToDate chapter (money to author); other, payment for blinded examiner on different studies (money to author) T.J.D. Departments of Physical Medicine and Rehabilitation and Clinical Neurological Sciences, Western University, London, Ontario, Canada Disclosure: nothing to disclose P.R.B. Department of Neurology, University of Ottawa, Ottawa, Ontario, Canada Disclosures outside this publication: consultancy, Baxter Advisory board meeting for IVIG, no relation to present paper (money to author and institution); expert testimony, expert witness opinion in legal case, Canadian medical protective association, 2013 (money to author); payment for lectures including service on speakers bureaus, The Ottawa Hospital CME, small speaker honoraria (money to author)
M.R. Department of Medicine, McGill University, Montreal, Quebec, Canada Disclosures outside this publication: grants/grants pending, US Department of National Defense spinal cord injury study (money to institution) R.J.F. Department of Medicine, McGill University, Montreal, Quebec, Canada Disclosures outside this publication: payment for lectures including service on speakers bureaus, speaking honorariums for conferences (money to author) M.B. Department of National Defence, Canadian Forces Health Centre, Ottawa, Ontario, Canada Disclosure: nothing to disclose E.S. Radiology Department, Montfort Hospital, Ottawa, Ontario, Canada Disclosure: nothing to disclose P.J.B.D. Department of Neurology, Mayo Clinic, Rochester, MN Disclosure: nothing to disclose Submitted for publication August 29, 2014; accepted May 1, 2015.
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Case Presentation
Diabetic Cranio-Cervico-Radiculoplexus Neuropathy Gaurav Gupta, MD, FRCPC, Rami Massie, MD, FRCPC, Timothy J. Doherty, MD, PhD, FRCPC, P.R. Bourque, MD, FRCPC, Mohan Radhakrishna, MD, FRCPC, Roderick J. Finlayson, MD, FRCPC, Markus Besemann, MD, FRCPC, LTC, Emmanuel Simantirakis, MD, FRCPC, P. James Bonham Dyck, MD
Abstract We describe a case of a 53-year-old man with type 2 diabetes mellitus in whom cervical-radiculoplexus neuropathy developed, with concomitant cranial and phrenic nerve involvement, occurring as a stepwise, monophasic course. The patient had a presumed remote history of idiopathic cervical-radiculoplexus neuropathy.
Introduction Recent reports suggest that diabetic cervicalradiculoplexus neuropathy (DCRPN) is a distinct entity when compared with idiopathic CRPN [1]. Radiculoplexus neuropathy (RPN) is likely an immunemediated microvasculitis resulting in ischemic axonal damage. It can affect patients with or without diabetes and can manifest at the cervical level (ie, CRPN), thoracic level (ie, thoracic radiculoneuropathy), and lumbar level (ie, lumbosacral radiculoplexus neuropathy [LRPN]) [2-4]. Case Description A 53-year-old man with right hand dominance presented with a 1-month history of right upper extremity pain and paresthesias. His medical history included type 2 diabetes mellitus (DM) with no known microvascular complications, previous right “viral” upper trunk brachial plexopathy at age 19 years with full functional and neurologic recovery, dyslipidemia, pigmented villonodular synovitis, and shoulder dislocation. Medications included rosuvastatin and metformin. He had no family history of brachial plexopathy. The patient described severe right posterolateral arm pain and paresthesias involving digits 1-3, followed by
weakness in the right triceps 1 week later. A physical examination completed 6 weeks after the onset of symptoms showed severe weakness of the triceps (Medical Research Council [MRC] grade 2/5), with mild weakness of the deltoid, supraspinatus, infraspinatus, flexor carpi radialis, and pronator teres (MRC grade 4þ/5). This weakness was accompanied with a decrease in the right triceps reflex and impaired sensation over the dorsal aspect of the arm and thumb. At 3 months from symptom onset, he had much less right upper arm pain, but his triceps strength had decreased. New-onset forearm and hand pain/allodynia also developed, along with severe hand intrinsic weakness. His physical examination at this time showed sensory abnormalities in the lateral aspect of the forearm and the entire hand, along with weakness of triceps (0/5), extensor carpi ulnaris (1/5), pronator teres (3/5), abductor pollicis brevis (3/5), flexor digitorum longus (median fibers) (0/5), flexor pollicis longus (0/5), flexor carpi radialis (0/5), and first dorsal interosseous (3/5). He also had mild weakness of the biceps (4/5), extensor carpi radialis (4e/5) and supinator (4/5), along with a decreased right triceps and quadriceps reflex. At 5-month follow-up, the patient reported improved upper arm pain and triceps weakness (MRC grade 1/5) but a 20-lb weight loss and ongoing hand pain and weakness. At 6 months after the onset of symptoms,
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diplopia developed that was worse with distance, with mild restriction of right eye abduction, which persisted for approximately 1 week and then resolved. At 1 year and 4 months after symptom onset, he had minor distal hand pain and improved triceps strength (3/5), with ongoing moderate hand weakness. At no point did he experience any autonomic symptoms. Relevant blood work to rule out a metabolic, infectious, and inflammatory condition was negative. Hemoglobin A1C performed 2 years prior to onset of symptoms was 0.063 (normal, 0.048-0.060). A chest radiograph showed right hemidiaphragm elevation and left Zung scarring/atelectasis. Magnetic resonance imaging (MRI) scans of the cervical spine, brachial plexus, and brain (with and without contrast enhancement) and shoulder (without contrast enhancement) were normal. A positron emission tomography scan was negative. These procedures were all performed within the first 6 months of the patient’s initial presentation. The patient refused to undergo a lumbar puncture to evaluate his cerebrospinal fluid. Electrodiagnostic tests are reported in Table 1. Genetic testing for peripheral myelin protein 22 (PMP-22) deletion or septin 9 apoprotein (SEPT9) mutation was not performed. Treatment focused on pain control using neuropathic pain medications (gabapentin, nortriptyline, and naproxen) and opioids (oxycodone, immediate and controlled release). The patient refused treatment with intravenous high-dose methylprednisolone. Discussion RPN was first described in 1890 by Bruns but has been known by other names over the years, including diabetic myelopathy, diabetic amyotrophy, diabetic polyradiculopathy, femoral and femoral-sciatic neuropathy of diabetes, proximal diabetic neuropathy, diabetic lumbosacral plexopathy, Bruns-Garland syndrome, diabetic motor or paralytic neuropathy, and diabetic mononeuritis multiplex [1,3]. Nomenclature inconsistency is mirrored by the variability in clinical presentation included in the spectrum of this condition, with some authors describing proximal limb involvement and others discussing multifocal, widespread presentations involving distal regions or a focal/unilateral condition progressing to a more widespread distal process [3,4]. Differential Diagnosis Various types of neuropathies related to diabetes have been described. These neuropathies can be subdivided according to pathophysiology: metabolic-microvascularhypoxic (eg, polyneuropathy and autonomic neuropathy), inflammatory/immune (eg, RPN, thoracic radiculoneuropathy, and diabetic cachexia), compressive (eg, median, ulnar, and/or peroneal mononeuropathies), complication-related (eg, neuropathy of ketoacidosis,
neuropathy of chronic renal failure, neuropathy with large vessel ischemia, and hypoglycemic neuropathy) and treatment-related (eg, insulin neuritis and hyperinsulin neuropathy) [5,6]. In diabetic or nondiabetic patients, peripheral neuropathic cause of unilateral upper limb pain, weakness, and sensory changes include idiopathic neuralgic amyotrophy (INA; eg, Parsonage-Turner syndrome), compressive and infiltrative brachial plexopathies, hereditary neuralgic amyotrophy (HNA), and neurogenic thoracic outlet syndrome [7]. In this case, a differential diagnosis of INA and HNA should be considered. Both conditions have been reported to occur in a stepwise and/or polyphasic course and have involvement of nerves outside of the brachial plexus. Based on their results, van Alfen and van Engelen [8] advocate that INA be considered a “mononeuropathia multiplex” with preferential involvement of specific regions. It is also likely that the underlying cause is immune, and therefore it follows that CRPN and INA refer to the same clinical entity. CRPN offers a more accurate clinical description than “amyotrophy,” “Parsonage-Turner syndrome” or “neuritis” [8]. Although INA/CRPN has been described to occur in both a stepwise and polyphasic course, to our knowledge, hereditary neuralgic amyotrophy has not been specifically associated with a stepwise presentation or weight loss [8]. The lack of a family history, although not excluding HNA, also makes it less likely. Specific genetic testing may have helped to alleviate further diagnostic confusion. It was not performed because it was not readily available at the time and would not have appreciably changed our management in this case. Should this patient have a recurrence, we can consider genetic testing at that time. Epidemiology RNP can occur in a small percentage of diabetic patients but is also described in nondiabetic patients [3,4]. It can affect patients between 36 and 76 years of age, with the average being 65 years [3,4]. RPN is more common in patients with type 2 DM compared with patients with type 1 DM. When compared with patients who have diabetic polyneuropathy, patients with diabetic RPN tends to have better controlled diabetes, short duration of diabetic disease (eg, median time to onset of 4 years), and possibly even be diagnosed with diabetes after RPN presentation. Patients have lower associated body mass index and a lower likelihood of insulin utilization and systemic complications (ie, nephropathy, retinopathy, and cardiovascular disease) [3,4]. Symptomatology Patients often present with acute or subacute severe, asymmetric, limb, or thoracic pain and paresthesias
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Table 1 Electrodiagnostic studies Region
1 Month After Symptom Onset
3 Months After Symptom Onset
4 Months After Symptom Onset
Median
NCS Mild decreased CMAP
NCS Normal CMAP EMG Acute (new) pronator teres (PSW, FP, RR)
NCS Severe decreased CMAP and forearm conduction block Absent SNAP digit 3 EMG Acute denervation FPL, FCR (PSW, FP, RR)
Radial
NCS Decreased CMAP and proximal block SNAP normal EMG Acute denervation triceps (PSW, FP, RR)
NCS Decreased SNAP 50% Decreased CMAP 70%
EMG Acute denervation EI, triceps (PSW, FP, RR)
Axillary
EMG Deltoid denervation (PSW, polyphasia)
Ulnar
EMG Deltoid PSW, CRD, and CD NCS Decreased CMAP
NCS Further decrease CMAP SNAP decrease 40% EMG Acute denervation FDI (PSW, FP, RR)
Miscellaneous
NCS Decreased right SNAP-MAC EMG Right C7 denervation PS (PSW, FP)
NCS Decreased radial CMAP for ERB stimulation EMG Right C7 denervation PS (PSW, FP)
NCS Right peroneal normal EMG Normal thoracic and lumbar PS
Conclusion/differential diagnosis
Right C7 radiculopathy vs middle trunk plexopathy CTS Chronic upper trunk plexopathy
Middle trunk plexopathy Diabetes-related paraspinal denervation ? Ulnar neuropathy at elbow
Diabetic craniocervical-radiculoplexus neuropathy
NCS ¼ nerve conduction studies; CMAP ¼ compound motor action potential; EMG ¼ electromyography; PSW ¼ positive sharp waves; FP ¼ fibrillation potentials; RR ¼ reduced recruitment; SNAP ¼ sensory nerve action potential; FPL ¼ flexor pollicis longus; FCR ¼ flexor carpi radialis; EI ¼ extensor indices proprius; MU ¼ motor unit; CD ¼ chronic denervation (large amplitude, long duration, polyphasic units, reduced recruitment); CRD ¼ complex repetitive discharge; FDI ¼ first dorsal interosseous; MAC ¼ medial antebrachial cutaneous; C7 ¼ 7th cervical nerve root; ERB ¼ extensor carpi radialis brevis; PS ¼ paraspinal; CTS ¼ carpal tunnel syndrome.
followed by weakness that evolves over weeks to months. The course has been defined as monophasic when neurologic symptoms/signs occur within 1 year of symptom onset [1,3,4]. As in this case, up to 21% of patients can have a stepwise course within the same year, and another 21% have been described as having recurrent symptoms and/or signs after more than 1 year of clinical stability (ie, a polyphasic course) [1]. In the case of our patient, this current episode could represent a recurrence of his previously described “viral upper trunk plexopathy” that he experienced at age 19 years. In the current episode, although he had stepwise-type worsening of symptoms at 3 and 6 months after presentation, the entire episode lasted less than 1 year. Until recently, most studies reported cervical/upper limb involvement primarily in association with co-existing lumbar/lower limb involvement [1]. In persons with LRPN, sensory and motor loss commonly occurs in a femoral/ obturator greater than sciatic nerve distribution, usually
beginning proximally, and then spreading distally and/or contralaterally. Associated symptoms can include weight loss of more than 10 lb, back pain, and autonomic dysfunction in up to 50% of patients [1,4]. Compared with persons who have diabetic LRPN, persons who have DCRPN present in a similar fashion, with very severe pain followed by disabling weakness and associated autonomic symptoms and weight loss. Small differences include more frequent weakness and/or reports of sensory symptoms at onset, more frequent associated phrenic or cranial neuropathies, and less frequent weight loss and bilateral spread in persons with DCRPN [1]. In one DCRPN cohort, more than 50% of patients had involvement outside the brachial plexus, and particularly relevant to our case, the phrenic nerve was involved in 5 of 80 patients and cranial nerves were involved in 2 of 80 patients [1]. Based on this same recent work, compared with persons with idiopathic CRPN, patients with DCRPN more frequently have
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Diabetic Cranio-Cervico-Radiculoplexus Neuropathy
associated weight loss, autonomic features, bilateral disease, and lower trunk and diffuse regional involvement [1]. This phenotypic difference, along with the much higher co-occurrence of thoracic RPN and LRPN, form the basis for considering DCRPN as a distinct clinical entity from CRPN. Diagnostic Studies Nerve conduction studies are characterized by an axonal loss pattern with reduction of compound motor amplitudes, sensory amplitudes, and slowing consistent with an axonal process. Electromyographic findings show neuropathic changes found in an asymmetric, multifocal pattern, which includes multiple myotomes, paraspinal muscles, and regions that may not be clinically affected. Autonomic and quantitative sensory testing can be abnormal, but is not necessarily diagnostic [3,4]. Laboratory abnormalities can include an elevated erythrocyte sedimentation rate, rheumatoid factor, antinuclear antibodies, and cerebrospinal fluid protein without pleocytosis. Nerve roots and plexus enhancement can be seen on MRI, but imaging studies are most useful in ruling out compressive pathologic conditions (eg, tumor, hematoma, and compressive polyradiculopathy) [3,4]. MRI findings in the CRPN can show increased T2 signal, contrast enhancement, and nerve hypertrophy [1]. Pathophysiology/Histology All nerve subtypes can be involved (ie, motor, sensory, and autonomic), and histologic findings of cutaneous sensory nerves are consistent with neural and vascular changes. The pattern of elevated inflammatory mediators (eg, neural factor kappa beta, intercellular adhesion moleculee1, tumor necrosis factorea, and interleukin 6) and, most importantly, the pathologic changes seen on nerve biopsies are suggestive of a small-vessel microvasculitis isolated to the peripheral nerves, but the exact cause has been extensively debated in the literature [3-5]. Treatment In uncontrolled trials, medication trials have included prednisone or intravenous immunoglobulin alone or in combination with other immunosuppressants (eg, azathioprine and cyclophosphamide), plasmapheresis, and intravenous methylprednisolone, with patients generally showing improvements in pain, weakness, and/or function [3,4]. In a double-blind, randomized, controlled trial, intravenous methylprednisolone, when compared with placebo, improved neuropathic pain and provided lower limb neurologic recovery 30 days sooner. It was also suggested that initiation of treatment within 3 months may lead to better outcomes overall [9].
Supportive treatment is important in the management of these conditions, including analgesics, physical therapy, education, home safety assessments, bracing, personal care, and mobility aids [3,4]. Outcomes Most patients achieve spontaneous partial recovery even without treatment by 18 months. Pain generally subsides within weeks to a few months, followed by a slow, gradual improvement in motor function. The motor recovery is usually incomplete, especially for distal weakness, and may have a variable impact on function [4]. As described here, up to one fifth of patients can have a multiphasic course, whereas another one fifth of patients can have recurrent episodes of pain and weakness after a year of clinical stability [1,3,4]. Conclusion CRPN is an immune-mediated vasculitis that can occur in diabetic and nondiabetic patients. The patient in this case had a stepwise, monophasic illness that included involvement of his cervical plexus and cranial nerves. Investigations were noncontributory and treatment was conservative, leading to partial distal motor recovery. Although a genetic cause could not be formally excluded, especially given his previous episode at age 19 years, the stepwise course within the same year, involvement of other body regions (phrenic and cranial neuropathies), associated weight loss, and associated DM favor the diagnosis of DCRPN. References 1. Massie R, Mauermann ML, Staff NP, et al. Diabetic cervical radiculoplexus neuropathy: A distinct syndrome expanding the spectrum of diabetic radiculoplexus neuropathies. Brain 2012;135: 3074-3088. 2. Dyck PJ, Norell JE, Dyck PJ. Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus neuropathy. Neurology 1999;53: 2113-2121. 3. Dyck PJ, Windebank AJ. Diabetic and nondiabetic lumbosacral radiculoplexus neuropathies: New insights into pathophysiology and treatment. Muscle Nerve 2002;25:477-491. 4. Bhanushali MJ, Muley SA. Diabetic and non-diabetic lumbosacral radiculoplexus neuropathy. Neurol India 2008;56:420-425. 5. Tracy JA, Dyck PJ. The spectrum of diabetic neuropathies. Phys Med Rehabil Clin N Am 2008;19:1-26. 6. Sinnreich M, Taylor BV, Dyck PJ. Diabetic neuropathies. Classification, clinical features, and pathophysiological basis. Neurologist 2005;11:63-79. 7. Khadilkar SV, Khade SS. Brachial plexopathy. Ann Indian Acad Neurol 2013;16:12-18. 8. van Alfen N, van Engelen BG. The clinical spectrum of neuralgic amyotrophy in 246 cases. Brain 2006;129:438-450. 9. Dyck PJ, Bosch PE, Grant I, et al. The multi-center double-blind controlled trial of IV methylprednisolone in diabetic lumbosacral radiculoplexus neuropathy. Neurology 2006;66(Suppl 2):A191.
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Disclosure G.G. Department of Medicine, McGill University, Montreal, Quebec, Canada; Department of National Defence, Canadian Forces Health Centre, Ottawa, Ontario, Canada; Alan Edwards Pain Management Unit, Montreal General Hospital, 1650 Ave Cedar, Montreal, Quebec, Canada H3G-1A4. Address correspondence to: G.G.; e-mail: [email protected] Disclosures outside this publication: grants/grants pending, Ultrasound Study (money to institution); payment for lectures including service on speakers bureaus, speaking honorariums for conferences (money to author) R.M. Department of Neurology, University of Montreal, Montreal, Quebec, Canada Disclosures outside this publication: payment for lectures including service on speakers bureaus, multiple lectures paid for by different drug companies (money to author); royalties, Author for UpToDate chapter (money to author); other, payment for blinded examiner on different studies (money to author) T.J.D. Departments of Physical Medicine and Rehabilitation and Clinical Neurological Sciences, Western University, London, Ontario, Canada Disclosure: nothing to disclose P.R.B. Department of Neurology, University of Ottawa, Ottawa, Ontario, Canada Disclosures outside this publication: consultancy, Baxter Advisory board meeting for IVIG, no relation to present paper (money to author and institution); expert testimony, expert witness opinion in legal case, Canadian medical protective association, 2013 (money to author); payment for lectures including service on speakers bureaus, The Ottawa Hospital CME, small speaker honoraria (money to author)
M.R. Department of Medicine, McGill University, Montreal, Quebec, Canada Disclosures outside this publication: grants/grants pending, US Department of National Defense spinal cord injury study (money to institution) R.J.F. Department of Medicine, McGill University, Montreal, Quebec, Canada Disclosures outside this publication: payment for lectures including service on speakers bureaus, speaking honorariums for conferences (money to author) M.B. Department of National Defence, Canadian Forces Health Centre, Ottawa, Ontario, Canada Disclosure: nothing to disclose E.S. Radiology Department, Montfort Hospital, Ottawa, Ontario, Canada Disclosure: nothing to disclose P.J.B.D. Department of Neurology, Mayo Clinic, Rochester, MN Disclosure: nothing to disclose Submitted for publication August 29, 2014; accepted May 1, 2015.