Background The prevalence and outcome of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in patients with solid organ transplantation is unknown, and there are no guidelines for the evaluation and treatment of such patients.
Methods An 8 year long monocentric prospective study was conducted in which, in a population of 1557 solid organ transplant recipients, the characteristics of 10 consecutive patients (0.6%) who developed a syndrome that fulfilled the clinical, biological and electrophysiological criteria for definite CIDP were investigated.
Results Five patients had liver transplantation, three had kidney transplantation, one had heart transplantation and one had lung transplantation. The mean interval between transplantation and CIDP was 10 months. Six patients developed CIDP after immunosuppressive therapy dosage was decreased and were treated with intravenous immunoglobulin (IVIG) and increased dosage of immunosuppressive therapy. Four patients were treated with IVIG only. Neuropathy improved in all cases, and CIDP had a monophasic course in all patients, with no relapse observed over a mean follow-up of 5 years.
Conclusion CIDP in solid organ transplant recipients is rare, appears in the first year after transplantation, has a monophasic course and is responsive to IVIG treatment. CIDP being treatable, it should be systematically considered in solid organ transplant recipients who develop a rapidly disabling sensorimotor polyneuropathy.
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Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a clinically heterogeneous sensory and motor neuropathy with a monophasic, relapsing or progressive course.1–3 CIDP develops over more than 8 weeks, distinguishing it from Guillain–Barré syndrome (GBS), which has an acute onset.1–3 CIDP is considered to have an immune basis, with inflammatory mediated demyelination being its hallmark.1–3 Numerous diseases have been described in association with CIDP, including diabetes mellitus, monoclonal gammapathy, HIV infection, bone marrow transplantation and systemic lupus erythematosus.1 CIDP associated with these diseases is usually considered as not being different from idiopathic CIDP, and patients are treated no differently.1–3 Steroids and intravenous immunoglobulin (IVIG) are an effective treatment for CIDP, with plasma exchange being a useful rescue therapy.1–3
CIDP has rarely been observed in solid organ transplant recipients under immunosuppressive therapy, and there are no guidelines for the evaluation and treatment of such patients.4–6
We report the results of an 8 year long monocentric prospective study in which we investigated the clinical characteristics and outcome of 10 consecutive solid organ transplant recipients who developed CIDP.
Patients and methods
Neurological management of patients before and after solid organ transplantation
Electrodiagnostic (EDX) studies are systematically performed during the pretransplantation evaluation at Strasbourg University Hospital. When polyneuropathy is diagnosed, disability grade is assessed using the Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale.7 Disability is scored as follows: for upper limbs, stage 0=normal, 1=symptoms in one or both arms, not affecting the ability to perform certain functions (all zips and buttons; washing or brushing hair; using a knife and fork together; and handling small coins), 2=symptoms in one arm or both arms, affecting but not preventing any of the above mentioned functions, 3=symptoms in one arm or both arms, preventing one or two of the above mentioned functions, 4=symptoms in one arm or both arms, preventing three or all of the functions listed, but some purposeful movements still possible, 5=inability to use either arm for any purposeful movement; for lower limbs, stage 0=normal, 1=walking affected, but walks independently outdoors, 2=usually uses unilateral support (stick, single crutch, one arm) to walk outdoors, 3=usually uses bilateral support (sticks, crutches, frame, two arms) to walk outdoors, 4=usually uses wheelchair to travel outdoors, but able to stand and walk a few steps with help, 5=restricted to wheelchair, unable to stand and walk a few steps with help; overall disability=sum of arm and leg disability, with a maximum disability score of 10. In our experience, axonal polyneuropathy is found in 90% of patients before transplantation with alcoholic, diabetic and uraemic polyneuropathies representing the majority of cases (Echaniz-Laguna, unpublished data).
After transplantation, patients are followed-up regularly in the transplant outpatient clinic where surveillance of medication compliance and monitoring of biological tests are carried out by our medical and transplant coordinator teams. When presenting with progressive sensorimotor symptoms not attributable to pretransplantation polyneuropathy, solid organ transplant recipients are systematically referred to the neuromuscular centre for further evaluation and treatment.
Patients with CIDP involved in this study were all referred from the transplant outpatient clinic to the Neuromuscular Centre, University Hospital of Strasbourg, France, between 2003 and 2010, and prospectively recruited into our study. All patients were sent for assessment of suspected peripheral nerve disease and they all presented with progressive sensorimotor symptoms. The diagnostic procedures were conducted according to the Strasbourg University Hospital Ethics Committee and informed consent was obtained from all patients.
To be included in our study, solid organ transplant recipients had to be diagnosed with definite CIDP using the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) clinical, biological and electrophysiological criteria.1 According to these criteria, definite CIDP is defined as proximal and distal weakness, areflexia or hyporeflexia developing over more than 2 months, and albuminocytological dissociation on CSF analysis. Patients were diagnosed with typical definite CIDP when weakness was symmetric, and diagnosed with atypical definite CIDP when weakness was asymmetric.1 Patients with symptoms developing over <2 months (ie, patients with GBS), were excluded from this study. INCAT disability grade was determined for each patient included in our study at the time of CIDP diagnosis.
Clinical and biological assessment
When included in our study, all CIDP patients underwent standardised clinical examinations and biological tests, including evaluation of glucose plasma level, glycated haemoglobin (HbA1c) level, and hepatic, renal and thyroid function. Antiganglioside antibodies (including anti-GQ1b, GT1a, GT1b, GD1a, GD1b, GM1, GM2, GM3, asialo-GM1 and sulphatides), anti-MAG antibodies, antineuronal and anticerebellar antibodies, monoclonal gammapathy, Borrelia burgdorferi serology (Lyme disease) and cytomegalovirus (CMV) serology were investigated in all cases. All patients also underwent CSF examination, including evaluation of protein and cell content, gammaglobulin ratio, oligoclonal bands, intrathecal anti-Borrelia antibody index and tests for neurotropic viruses and syphilis.
When included in our study, EDX studies were performed in all CIDP patients and included nerve conduction study in the upper and lower limbs and electromyography using a concentric needle electrode in at least three muscles. Electrophysiological studies were performed using conventional equipment and standard methods, and skin temperature was maintained in the range 32–34°C. The amplitude of a sensory nerve action potential was measured peak to peak. Motor response amplitudes were measured from baseline to peak of the negative component and areas were measured by the computer program in the electromyography machine. When patients were diagnosed with CIDP and included in our study, pretransplantation EDX studies and INCAT disability grades were retrospectively reviewed.
In addition to the above mentioned clinical, biological and electrophysiological criteria, superficial peroneal nerve biopsy was performed in six patients to provide supportive evidence for the diagnosis of CIDP.1 Nerve biopsies were processed with standard methods for histology and electron microscopy, with special attention given to demonstrate evidence of demyelination and/or remyelination by electron microscopy (ie, onion bulb formation) and demyelinated and remyelinated nerve fibres. Endoneurial mononuclear cell infiltration and macrophage associated demyelination were also investigated. Teased fibre analysis was not performed.
After CIDP was diagnosed and treated, patients were followed-up jointly in the transplant outpatient clinic and neuromuscular centre. Neurological clinical evaluations were performed every 6 months after the initial neurological assessment, INCAT disability grade was evaluated 12 months after the initial neurological assessment and control EDX studies were performed 12 months after CIDP was diagnosed and treated.
One way analyses of variance (ANOVA) with repeated measures were used to compare peroneal nerve and sural nerve conduction velocity measured before transplantation, at the time of CIDP diagnosis and 1 year after CIDP diagnosis and treatment. When the F value indicated significant differences, a Student–Neuman–Keuls test for multiple comparisons was performed. The significance level was set at α=0.05.
Among 1557 patients with solid organ transplantation followed in our university hospital, 10 consecutive solid organ transplant recipients diagnosed with definite CIDP using the EFNS/PNS clinical, biological and electrophysiological criteria were prospectively enrolled in our study over an 8 year period (2003–2010) (figure 1). The general characteristics of the patients and the results of the clinical, biological and pathological evaluations are summarised in tables 1–3.
In comparison with the group of 1557 solid organ recipients followed in the transplant outpatient clinic (mean age 50 years; 64% men), patients in the CIDP group were older and predominantly male (mean age 60 years; 80% men). Two additional solid organ transplant recipients were not included in our study because they were diagnosed with probable (one case) and possible (one case) CIDP according to the EFNS/PNS guidelines.1 All patients had been transplanted in our hospital, and all patients walked with extreme difficulty at the time of diagnosis, with four patients being wheelchair bound most of time. Mean INCAT disability grade of the 10 patients at the time of CIDP diagnosis was 6.7/10.
Patients progressively developed CIDP with a mean interval of 10 months (3–36) between transplantation and first clinical sensorimotor symptoms. Six patients developed CIDP after immunosuppressive therapy dosage was decreased and were treated with five courses of IVIG, 0.4 g/kg daily, and increased doses of immunosuppressive therapy (tables 1–3). Four patients were treated with only five courses of IVIG (0.4 g/kg daily).
Lyme disease and CMV serology were negative in all patients, and no antibodies to myelin proteins and gangliosides were observed (table 3).
All patients met the EFNS/PNS electrophysiological criteria for primary demyelination (ie, a combination of reduced conduction velocities, prolonged distal latencies, abnormal F waves, partial motor conduction blocks and temporal dispersion) (table 4, figure 2). The retrospective review of the EDX studies performed before transplantation demonstrated chronic axonal sensorimotor polyneuropathy in eight patients (table 1).
Nerve pathological examination was performed in six patients and revealed abnormalities consistent with CIDP in all cases (ie, segmental demyelination and remyelination with onion bulbs and hypermyelinated fibres by electron microscopy) (figure 3). Mild to moderate axonal loss was also observed, most especially in patients who had been diagnosed with axonal polyneuropathy before transplantation (figure 3). Endoneurial mononuclear cell infiltration and macrophage associated demyelination were not observed.
Neuropathy significantly improved in all cases, and all patients were able to walk without assistance 12 months after CIDP onset. The mean INCAT disability grade of the 10 patients 12 months after CIDP onset was 4.4/10. Electrophysiological studies performed 12 months after CIDP onset in all patients demonstrated a significant improvement, with increased sensory and motor nerve conduction velocities. Mean peroneal nerve motor conduction velocity was higher before transplantation than at CIDP onset and at 1 year after CIDP (p<0.001 and p<0.05, respectively), and was lower at CIDP onset than at 1 year after CIDP (p<0.001) (figure 4). Similarly, mean sural nerve sensory conduction velocity was higher before transplantation than at CIDP onset and at 1 year after CIDP (p<0.01 and p<0.05, respectively), and was lower at CIDP onset than 1 year after CIDP (p<0.05) (figure 4). Taken together, these results indicate demyelination of peripheral nerves at the time of CIDP, with partial remyelination 1 year after diagnosis and treatment of the disease. In all patients, CIDP had a monophasic course with no relapse observed after a mean follow-up of 5 years.
Inflammatory neuropathies rarely occur in solid organ transplant recipients, with GBS being the most common cause.8 Solid organ transplant associated CIDP is rare, and to date only a few cases have been reported in the literature.4–6 In keeping with this concept, the 10 patients described here represented only 0.6% of 1557 patients who had solid organ transplantation in our hospital during the period 2003 to 2010.
The prevalence of CIDP is estimated as between 1 and 7.7 in 100 000 in the general population, with adult men being most frequently affected.2 3 9–13 The prevalence of CIDP is probably underestimated as a result of difficulty in diagnosis, under reporting of patients in remission and under reporting of patients with an associated condition.2 3 In our study, 0.6% of solid organ recipients from our university hospital developed CIDP, representing almost 100 times the published prevalence of CIDP in the general population.2 3 9–13 This observation suggests a non-coincidental association between CIDP and solid organ transplantation, with solid organ transplant recipients being at increased risk of developing CIDP in comparison with the general population.
Several factors may contribute for CIDP to develop in solid organ transplant recipients. For instance, it has been hypothesised that immunosuppressive therapy may trigger an inflammatory neuropathy by differential effects on T cell subsets.14 Tacrolimus (formerly known as FK506) and ciclosporin have both been described as provoking demyelinating polyneuropathy but both treatments have also been reported as having positive effects on patients with CIDP.1 2 14 15 Our patients continued to take ciclosporin and tacrolimus and remained stable, rendering both treatments unlikely causes of the neuropathy. Viral infections may also trigger inflammatory polyneuropathy in immunosuppressed patients. For instance, there is evidence of CMV infection in almost all reported cases of GBS in solid organ transplant recipients, suggesting that CMV may have a role in triggering this condition.8 In keeping with this concept, CIDP has also been described in association with chronic hepatitis C virus infection.5 The patients described here had no evidence of CMV infection, rendering CMV an unlikely cause of CIDP. However, two patients had chronic hepatitis C virus infection which may have contributed to triggering of CIDP.
We identified several factors that may have contributed towards solid organ transplant recipients developing CIDP. First, six patients developed CIDP after immunosuppressive therapy dosage was decreased, suggesting reduced immunosuppression triggered inflammatory polyneuropathy. Albeit not well known, the pathophysiology of CIDP involves T cell activation and antibodies to peripheral nerve proteins.2 3 Patients with CIDP have increased systemic concentrations of tumour necrosis factor α, interleukin 2, adhesion molecules, matrix metalloproteinases and chemokines. As tacrolimus, ciclosporin and prednisone reduce expression levels of many chemokines, one may hypothesise that reducing the treatment dosage may increase chemokine expression and trigger CIDP in predisposed subsets of patients.2 3 Second, eight patients presented with polyneuropathy before transplantation, and one may wonder whether chronic peripheral nerve damage may contribute to the pathophysiology of CIDP in solid organ transplant recipients. Cellular and humoural immunity are involved in CIDP physiopathology, and it could be hypothesised that CIDP may develop in solid organ transplant recipients as an autoimmune disease directed against chronically damaged peripheral nerves.2 3 Against this hypothesis, no antibodies to myelin proteins and gangliosides were observed in our patients. Furthermore, polyneuropathy is commonly observed in patients during pretransplantation evaluation. In our university hospital, axonal polyneuropathy is found in 90% of patients before transplantation (Echaniz-Laguna, unpublished data), contrasting with 0.6% of transplanted patients developing CIDP.
Nerve biopsy deserves special mention. Although there is only class IV evidence from uncontrolled studies concerning these matters, it is usually considered that nerve pathology can provide supportive evidence for the diagnosis of CIDP, with supportive features being macrophage associated demyelination, onion bulb formation, demyelinated and remyelinated nerve fibres, endoneurial oedema and endoneurial mononuclear cell infiltration.1 In the six cases with nerve biopsy presented here (patient Nos 1–6), nerve pathology was never absolutely typical of CIDP as it systematically demonstrated axonal loss in addition to classical demyelination features such as demyelination, remyelination, onion bulbs and hypermyelinated fibres (figure 3). Furthermore, endoneurial mononuclear cell infiltration and macrophage associated demyelination were never observed in our patients. These results are most likely explained by the fact that almost all transplanted patients who developed CIDP in our study presented with chronic axonal polyneuropathy before transplantation. These results also indicate that the diagnostic yield from nerve biopsy in transplanted patients with CIDP is low, leading us to abandon this procedure in the four other patients presented in this study (patient Nos 7–10).
The outcome of CIDP in solid organ transplant recipients was good and all patients recovered almost normal motor and sensory functions after being treated. In all patients, CIDP had a monophasic course with no relapse observed after a mean 5 years of follow-up. This time course is more reminiscent of GBS than CIDP, and one may wonder whether our patients presented with monophasic CIDP or prolonged GBS.1–3 16 In our study, several lines of evidence argue against our patients having GBS. First, by consensus, the minimum duration of symptoms for CIDP to be diagnosed is 2 months to distinguish it from GBS which evolves over <1 month.1–3 All of our patients had symptoms developing over more than 2 months, consistent with CIDP. Second, it has been demonstrated that a large subset (7–50%) of patients with CIDP have a monophasic illness, with only 20–35% of patients presenting with a relapsing form.2 3 All of our patients presented with a monophasic illness, which remains consistent with CIDP. Lastly, none of the patients described here presented with evidence of CMV infection, the latter being observed in almost all reported cases of GBS in solid organ transplant recipients.8
One may also wonder whether CIDP in solid organ transplant recipients is related to the recently described postsurgical inflammatory neuropathies.17 In the latter, neuropathy usually develops within 30 days of surgery, with electrophysiology demonstrating mainly axonal damage and nerve biopsy showing perivacular lymphocytic inflammation and microvasculitis in the majority of cases.17 In contrast, CIDP in transplanted patients typically develops several months after surgery, with electrophysiology and nerve biopsy demonstrating demyelination and axonal loss, with no sign of microvasculitis.
All in all, it seems to us that CIDP in solid organ transplant recipients is a distinct entity with unique pathophysiological, clinical and evolutive characteristics that clearly distinguish it from other neuropathies, such as CMV related GBS in transplanted patients and early postsurgical inflammatory neuropathies.
Our study demonstrates that CIDP in solid organ transplant recipients is a rare condition that usually appears in the first year after transplantation, has a monophasic course and is responsive to IVIG treatment. CIDP being treatable, it should be considered in all patients with solid organ transplantation who develop a rapidly disabling sensorimotor polyneuropathy.
The authors thank the patients. They also thank Michel Mohr (Department of Pathology, Strasbourg University Hospital) and Bernard Ellero (Department of Transplantation, Strasbourg university Hospital) for critical remarks and suggestions.
See Editorial commentary p 672
Competing interests JDS serves on scientific advisory boards for and has received honoraria from Biogen Idec, LFB, Merck Serono, Sanofi-Aventis and Bayer Schering Pharma, and serves on the editorial board of Revue Neurologique (Paris).
Patient consent Obtained.
Ethics approval Ethics approval was provided by the Hôpitaux Universitaires Strasbourg institutional review board.
Provenance and peer review Not commissioned; externally peer reviewed.