Chronic Inflammatory Demyelinating Polyneuropathy in Systemic Lupus Erythematosus: A Rare Entity



Rozita Mohd*, Fatimah Zanirah Nordin, Rizna Cader
Nephrology Unit, Pusat Perubatan Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000, Cheras Kuala Lumpur, Malaysia


Article Metrics

CrossRef Citations:
0
Total Statistics:

Full-Text HTML Views: 197
Abstract HTML Views: 132
PDF Downloads: 83
ePub Downloads: 107
Total Views/Downloads: 519
Unique Statistics:

Full-Text HTML Views: 147
Abstract HTML Views: 95
PDF Downloads: 60
ePub Downloads: 56
Total Views/Downloads: 358



© 2018 Mohd et al

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Nephrology Unit, Pusat Perubatan Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000, Cheras Kuala Lumpur, Malaysia; Tel: +60122022794; E-mail: rozi8286@gmail.com


Abstract

Background:

Neurological manifestations in Systemic Lupus Erythematous (SLE) varies and commonly affects the Central Nervous System (CNS) rather than the peripheral nervous system. Neuropsychiatric or CNS manifestation can be as high as 24-54%, whereas the peripheral nervous system involvement is lower around 5-27%. Chronic Inflammatory Demyelinating Polyradiculopathy (CIDP) is one of the three commonest peripheral nervous system involvements in SLE patients and results with severe debilitating effects. However, it is rarely reported.

Methods:

A retrospective review of all SLE patients that were diagnosed with CIDP between 2000 and 2015 was done under follow up at our center that were diagnosed with CIDP between 2000 and 2015. We reviewed their medical records and analyzed their clinical presentation, investigations, treatment instituted, response to therapy and any neurological sequealae.

Results:

A total of 512 case notes were reviewed. Of these 4 patients presented with CIDP (3 females, 1 male) aged between 26 to 46 years old. Three presented with transverse myelitis and the other one with acute motor and sensory axonal neuropathy. All patients were treated with high dose corticosteroids, three patients received cyclophosphamide whilst the other patient was induced with mycophenolate mofetil. Complete recovery was seen in one patient, two had persistent but improving numbness and the other one had a residual weakness.

Conclusion:

Peripheral nervous system involvement in SLE can result in serious debilitating effects. Early diagnosis and treatment are crucial in limiting the neurological sequealae.

Keywords: Chronic inflammatory demyelinating polyradiculopathy, cyclophosphamide, Neurological, Systemic lupus erythematous, Peripheral nervous system, Debilitating effects.



1. INTRODUCTION

Systemic Lupus Erythematosus (SLE) is an autoimmune disease which has diverse clinical manifestation. Neuropsychiatric manifestation of SLE has been reported to be as high as 14 to 80% in adults [1, 2]. The prevalence of peripheral nervous system involvement in SLE is not well established but studies have reported it to vary from 2-13.5%. [3, 4] Common polyneuropathy presentation in SLE includes multiple mononeuritis, acute inflammatory demyelinating polyneuropathy and chronic inflammatory demyelinating polyneuropathy [2]. Albeit rare, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is the commonest neurological entity associated with SLE and is being increasingly recognized [5, 6]. CIDP is a chronic, acquired, immune-mediated condition affecting the peripheral nervous system and is characterized by progressive limb weakness, sensory loss and areflexia with a relapsing or progressive course [7, 8]. The first case of CIDP was reported in 1958 in a patient presenting with recurring polyneuropathy that responded to corticosteroid therapy [9]. Subsequently, a diagnostic criteria was proposed by Dyck et al in 1975 following a 5-year observation in 53 patients with segmental demyelination [10]. In addition to SLE, CIDP may also be seen in patients with hepatitis C, HIV, malignancies and diabetes [11]. Standard treatment of CIDP is corticosteroids, intravenous immunoglobulin and plasmapheresis [8, 12]. Two-thirds of CIDP patients respond to standard treatment whereas one third can be refractory to the above treatment and may need other immunosuppressive therapies such as cyclophosphamide, mycophenolate mofetil, azathioprine cyclosporin, tacrolimus which can be used to limit corticosteroid and immunoglobulin use [12]. The prognosis in refractory cases is dismal.

Here, we review all our SLE patients that presented with CIDP and report on their clinical manifestations, treatment and progress, and a brief review of the literature on CIDP in SLE patients.

2. METHODOLGY

A retrospective review of all SLE patients (revised ACR criteria) that were under the nephrology clinic at our institution from year 2000 to 2015. We reviewed the case notes of all patients who were diagnosed with CIDP during the course of illness. Their demographic data were studied in particular looking into their clinical presentation, investigation pertaining to the diagnosis of CIDP, treatment instituted, response to therapy and any neurological sequealae. The diagnosis of CIDP was confirmed with either nerve conduction studies that were interpreted by a neurologist or radiological imaging.

We excluded SLE patients with other known causes of neuropathy such as diabetes mellitus, chronic kidney disease and vitamin deficiencies.

3. RESULTS

A total of 512 patients with lupus nephritis were followed up at our institution within this 15 year period. Of these, 4 patients had presented with a diagnosis of peripheral nervous system involvement and their cases are summarized below.

- Case 1 Case 2 Case 3 Case 4
Age/Gender 46/M 26/ F 35/F 33/F
SLE diagnosis (year) 2008 2007 1998 1999
Onset of CIDP post SLE Diagnosis (months) 8 months 8 months 7 years 13 years
CIDP symptoms Bilateral quadriceps weakness, normal sensation, normal reflexes Numbness of right upper limb with loss sensation, light touch and pinprick (C6-T1) and absent reflexes Bilateral intermittent upper limb numbness with progressive bilateral lower limb weakness. Neuropathic pain affecting all 4 limbs, with reduced power in both limbs with hyperreflexia
Durations of symptoms 2 weeks 3 weeks One year 2 weeks
EMG/MRI findings LP: elevated protein,
no oligoclonal bands
MRI Brain and Spine: normal
NCS: axonal and sensory polyneuropathy
LP: elevated protein
MRI Spine: normal
NCS: normal
LP: elevated protein, no oligoclonal bands
MRI Brain: normal
MRI Spine: transverse myelitis hyper intense lesion C3-T2
LP: normal,
no oligoclonal bands
MRI Spine: hyper intense lesion C5-C7 with cord oedema
Concomitant manifestations LN Class IV MSK
LN Class IV
Cerebral lupus
MSK
LN Class III
MSK
LN III/V
Antibodies
(at diagnosis)
C3(NR:86-185 mg/dL)
C4(NR:20-59 mg/dL)
C3 69.2 mg/dL
C4 21.7mg/dL
ANA 1:640
Anti dsDNA negative
ACL negative
C3 24.5 mg/dL
C4 < 10 mg/dL
ANA 1:320
Anti dsDNA positive
ACL negative
C3 49.6 mg/dL
C4 < 10 mg/dL
ANA 1:160
Anti dsDNA negative
ACL negative
C3 99.2 mg/dL
C4 14.1 mg/dL
ANA 1:160
Anti dsDNA positive
ACL negative
Treatment Corticosteroids,
Mycophenolate mofetil, gabapentin
Corticosteroids,
Plasmapheresis,
IV Immunglobulin
IV Cyclophosphamide for one year then maintained with mycophenolate mofetil and ciclosporin A
Corticosteroids,
Plasmapheresis,
IV Immunoglobulin, IV cyclophosphamide
then maintained with mycophenolate mofetil
Corticosteroids,
IV cyclophosphamide then maintained with myfortic and tacrolimus
Outcome Symptoms resolved gradually over one year Relapsed with new onset of numbness & reduced sensation in
T4 -T10 dermatomes whilst on treatment with IV
cyclophosphamide
for 18 months
Six months later symptoms recurred and repeat MRI demonstrated transverse myelitis C1-C7
Persistent numbness despite SLE being in complete remission but ADL independent
Relapsed 8 years later with generalized tonic clonic seizures and bilateral numbness and weakness of both limbs with hyperreflexia.
MRI Brain and Spine: hyperintense C3- T3 lesions
Treated as relapsed CNS lupus with IV cyclophosphamide
Symptoms persist but ADL independent
Symptoms improved gradually over 6 months
Follow up (years) 8 years 7 years 18 years 17 years

4. DISCUSSION

CIDP in SLE patients has been increasingly gathering the attention of clinicians despite its unclear pathophysiology. It is believed to be an autoimmune condition whereby there is the production of antibodies against gangliosides (especially towards GM1 and GM3) [8]. These antibodies destroy the myelin sheath and axon resulting in polyneuropathy [13]. The prevalence of CIDP is between 2-5 cases/100,000 individuals in the general population but there is no data in SLE patients [14]. Neuropsychiatric syndromes of SLE in adults develop before or around the diagnosis SLE in 30-70% of patients [15, 16]. Two of our patients developed CIDP around the time of SLE diagnosis whereas in the other two, it developed many years later during the course of their disease.

The clinical presentation of CIDP varies depending on the nerve involvement as illustrated in our case series. Typically they either present with chronic progressive, stepwise progressive or relapsing weakness with symmetrical involvement of proximal and distal muscles and sparing of extraocular muscles [10, 17]. Even though our case series is in a younger age group, they had a chronic progressive course like the reported literature in the majority of elderly patients with CIDP [18]. CIDP can mimic Guillian Barre syndrome but they rarely develop respiratory failure and is not preceded by an infection [19, 20].

Pure motor presentation affects up to 10% of cases whilst the sensory variant affects 35% of the cases whereas the remaining 50% present with a combination of sensory and motors symptoms [21, 22]. Three out of our four patients presented with sensory symptoms and three had weakness. In case 1, he exhibited typical bilateral symmetrical motor neuropathy with normal sensory while case 4 developed limbs weakness with hypereflexia. Case 2 had areflexia with sensory involvement however power was relatively normal. In all the cases reported, case 3 was the one that exhibited most manifestations of neuropsychiatric SLE ranging from cerebral lupus, mood disorders, seizures, aseptic meningitis to CIDP.

The most important laboratory studies that support the diagnosis of CIDP are Cerebrospinal Fluid (CSF) examination, Nerve Conduction Studies (NCS) and Magnetic Resonance Imaging (MRI). Of these CSF evaluation is the most sensitive as protein is elevated in up to 94% of cases and in keeping with our findings [23]. Oligoclonal bands are identified in the CSF in up to 65% of CIDP patients but we did not demonstrate this in our patients [11]. Nerve conduction studies or electromyography is the investigation of choice to confirm the diagnosis of CIDP. However, it bears no significance or impact in terms of severity or prognosis of CIDP. Only two of our patients had NCS as the other two patients had MRI findings in keeping with CIDP. Typical MRI findings include thickened or swollen gadolinium enhancing roots or plexuses on a T2 weighted image [11]. Such findings were present in three of our patients either during initial presentation or relapse.

Studies have demonstrated positive anticardiolipin antibody of IgG and IgM has a strong correlation with neurological lesions detected by the electromyography than those without antibodies [24]. However, in our case series, we could not demonstrate this finding.

Treatment goals are to improve muscle strength and patients’ quality of life [8]. Corticosteroids are used as first-line due to its anti-inflammatory properties and all our patients received high dose corticosteroids. An alternative to corticosteroids is Intravenous Immunoglobulin (IVIG) for 3 to 5 days with or without Plasma exchange [7, 8, 12].IVIG responder could see the effect within 1-3 months and it is best used if the symptoms occurred less than one year with extremities involvement, however, the response was reported to be poor in those with multiorgan involvement with multiple SLE autoantibodies [16]. In our case series, two patients received IVIG with plasmapharesis in addition to steroid treatment.

Studies have shown that about one-third of CIDP patients will be partially responsive or refractory to standard mentioned therapy requiring second-line immunosuppressive therapy such as azathioprine, cyclosporin A, mycophenolate Mofetil or cyclophosphamide [8]. Intravenous pulsed Cyclophosphamide in both intravenous pulsed or oral has been shown to be effective in patients’ refractory to IVIG, plasma exchange or corticosteroids with an average time for improvement to be 8.5 months [25, 26]. We chose cyclophosphamide in three of our patients as a second line agent as they also had concomitant lupus nephritis for which it is the mainstay of induction therapy. These patients were then maintained on with mycophenolate mofetil ± calcineurin inhibitor together with low dose corticosteroid.

Anecdotal reports have shown promising effects with monoclonal antibodies such as Rituximab, Alemtuzumab and Eculizumab [8]. Rituximab is more widely reported compared to the other biologics and been used either as first line or as an adjunct treatment in refractory cases. Rituximab is an anti CD 20 antibody on B-lymphocytes which causes depletion of B cells resulting in a reduction of antigen-antibody complex. Few studies have reported a satisfactory response with rituximab in patients with refractory CIDP [27-29]. In our cases, none of them received rituximab despite case 3 being counseled for it.

Studies have shown that 90% of CIDP patients respond to immunosuppressive therapy however they have a high relapse rate of up to 50% [23]. The 2007 CIDP outcomes survey demonstrated that despite advances in the treatment and care of CIDP patients, neurological prognosis remains poor with majority end up with some degree of disability and one-third of them require an assistive device to ambulate [30]. In our case series, two of our four patients had persistent symptoms but were able to ambulate unaided.

CONCLUSION

There are still limited numbers of randomized clinical trials on CIDP in SLE in view of its scarcity. Our case series describes the clinical presentation, diagnostic tools used, the therapeutic armamentarium and outcomes in CIDP. We believe cyclophosphamide is safe and efficacious in treating CIDP. Early diagnosis and treatment are crucial in limiting the neurological sequealae.

ETHICAL APPROVAL AND CONSENT TO PARTICIPATE

Not applicable.

HUMAN AND ANIMAL RIGHTS

No animals/humans were used for the studies that are bases of this research.

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

The authors declare that there is no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

REFERENCES

[1] Ainiala H, Loukkola J, Peltola J, Korpela M, Hietaharju A. The prevalence of neuropsychiatric syndromes in systemic lupus erythematosus. Neurology 2001; 57(3): 496-500.
[2] Unterman A, Nolte JE, Boaz M, Abady M, Shoenfeld Y, Zandman-Goddard G. Neuropsychiatric syndromes in systemic lupus erythematosus: A meta-analysis. Semin Arthritis Rheum 2011; 41(1): 1-11.
[3] Bertsias GK, Ioannidis JP, Aringer M, et al. EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: Report of a task force of the EULAR standing committee for clinical affairs. Ann Rheum Dis 2010; 69(12): 2074-82.
[4] Florica B, Aghdassi E, Su J, Gladman DD, Urowitz MB, Fortin PR. Peripheral neuropathy in patients with systemic lupus erythematosus. Semin Arthritis Rheum 2011; 41(2): 203-11.
[5] Hsu TY, Wang SH, Kuo CF, Chiu TF, Chang YC. Acute inflammatory demyelinating polyneuropathy as the initial presentation of lupus. Am J Emerg Med 2009; 27(7): 900.e3-5.
[6] Zoilo MA, Eduardo B, Enrique F, del Rocio MV. Chronic inflammatory demyelinating polyradiculoneuropathy in a boy with systemic lupus erythematosus. Rheumatol Int 2010; 30(7): 965-8.
[7] Köller H, Kieseier BC, Jander S, Hartung HP. Chronic inflammatory demyelinating polyneuropathy. N Engl J Med 2005; 352(13): 1343-56.
[8] Dalakas MC. Advances in the diagnosis, pathogenesis and treatment of CIDP. Nat Rev Neurol 2011; 7(9): 507-17.
[9] Austin JH. Recurrent polyneuropathies and their corticosteroid treatment; with five-year observations of a placebo-controlled case treated with corticotrophin, cortisone, and prednisone. Brain 1958; 81(2): 157-92.
[10] Dyck PJ, Arnason BG. Chronic inflammatory demyelinating polyradiculoneuropathy.Peripheral neuropathy 1984; 2101-14.
[11] Dimachkie MM, Barohn RJ. Chronic inflammatory demyelinating polyneuropathy. Curr Treat Options Neurol 2013; 15(3): 350-66.
[12] Gorson KC. An update on the management of chronic inflammatory demyelinating polyneuropathy. Ther adv neurol disord 2012; 596: 359-73.
[13] Hafer-Macko CE, Sheikh KA, Li CY, et al. Immune attack on the Schwann cell surface in acute inflammatory demyelinating polyneuropathy. Ann Neurol 1996; 39(5): 625-35.
[14] Rajabally YA, Nicolas G, Piéret F, Bouche P, Van den Bergh PY. Validity of diagnostic criteria for chronic inflammatory demyelinating polyneuropathy: A multicentre European study. J Neurol Neurosurg Psychiatry 2009; 80(12): 1364-8.
[15] Muscal E, Brey RL. Neurologic manifestations of systemic lupus erythematosus in children and adults. Neurol Clin 2010; 28(1): 61-73.
[16] Vina ER, Fang AJ, Wallace DJ, et al. Chronic inflammatory demyelinating polyneuropathy in patients with SLE: Prognosis and outcome. Semin Arthritis Rheum 2005; 35(3): 175-84.
[17] Barohn RJ. Approach to peripheral neuropathy and neuronopathy. Semin Neurol 1998; 18(1): 7-18.
[18] Dyck PJ, Oviatt KF, Lambert EH. Intensive evaluation of referred unclassified neuropathies yields improved diagnosis. Ann Neurol 1981; 10(3): 222-6.
[19] Dionne A, Nicolle MW, Hahn AF. Clinical and electrophysiological parameters distinguishing acute-onset chronic inflammatory demyelinating polyneuropathy from acute inflammatory demyelinating polyneuropathy. Muscle Nerve 2010; 41(2): 202-7.
[20] Ruts L, Drenthen J, Jacobs BC, van Doorn PA. Distinguishing acute-onset CIDP from fluctuating Guillain-Barre syndrome: A prospective study. Neurology 2010; 74(21): 1680-6.
[21] Gorson KC, Allam G, Ropper AH. Chronic inflammatory demyelinating polyneuropathy: Clinical features and response to treatment in 67 consecutive patients with and without a monoclonal gammopathy. Neurology 1997; 48(2): 321-8.
[22] Sabatelli M, Madia F, Mignogna T, Lippi G, Quaranta L, Tonali P. Pure motor chronic inflammatory demyelinating polyneuropathy. J Neurol 2001; 248(9): 772-7.
[23] Barohn RJ, Kissel JT, Warmolts JR, Mendell JR. Chronic inflammatory demyelinating polyradiculoneuropathy. Clinical characteristics, course, and recommendations for diagnostic criteria. Arch Neurol 1989; 46(8): 878-84.
[24] Nakajima H, Shinoda K, Doi Y, et al. Clinical manifestations of chronic inflammatory demyelinating polyneuropathy with anti-cardiolipin antibodies. Acta Neurol Scand 2005; 111(4): 258-63.
[25] Good JL, Chehrenama M, Mayer RF, Koski CL. Pulse cyclophosphamide therapy in chronic inflammatory demyelinating polyneuropathy. Neurology 1998; 51(6): 1735-8.
[26] Jasmin R, Sockalingam S, Shahrizaila N, Cheah TE, Zain AA, Goh KJ. Successful treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) in systemic lupus erythematosus (SLE) with oral cyclophosphamide. Lupus 2012; 21(10): 1119-23.
[27] Benedetti L, Briani C, Franciotta D, et al. Rituximab in patients with chronic inflammatory demyelinating polyradiculoneuropathy: A report of 13 cases and review of the literature. J Neurol Neurosurg Psychiatry 2011; 82(3): 306-8.
[28] Cocito D, Grimaldi S, Paolasso I, et al. Immunosuppressive treatment in refractory chronic inflammatory demyelinating polyradiculoneuropathy. A nationwide retrospective analysis. Eur J Neurol 2011; 18(12): 1417-21.
[29] Sanz PG, García Méndez CV, Cueto AL, et al. Chronic inflammatory demyelinating polyradiculoneuropathy in a patient with systemic lupus erythematosus and good outcome with rituximab treatment. Rheumatol Int 2012; 32(12): 4061-3.
[30] Koski CL, Baumgarten M, Magder LS, et al. Derivation and validation of diagnostic criteria for chronic inflammatory demyelinating polyneuropathy. J Neurol Sci 2009; 277(1-2): 1-8.