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Chronic inflammatory demyelinating polyradiculoneuropathie
03 February 2009

Authors

I.N. van Schaik, M.D., Ph.D.
P.A. van Doorn, M.D., Ph.D.


Clinical features

The first patients with CIDP are described already in 1911 by Werthein Salamon. Then the disease was named polyneuritis idiopathica subacuta. In the years to follow more of those patients were described by various neurologist. In 1958 Austin reviewed 32 cases of recurrent polyneuropathy and he pointed at the corticosteroid responsiveness in nine of these cases.1 Since some of these patients  turned out to be responsive to immunomodulating treatment, an overwhelming research effort has been put into trying to understand the mechanisms of disease, finding more effective and long-lasting therapies, and defining clear and practical criteria for the diagnosis.

CIDP is characterised by motor and/or sensory symptoms and signs in more than one limb, developing over at least two months.2-5 The disease runs a progressive, relapsing-remitting or monophasic course. Sensory disturbances are usually minor compared to the degree of weakness, but are found in approximately 80 per cent of patients. Predominantly motor involvement occurs in approximately 10-20%, predominantly sensory involvement has been reported but is rare.6;7 Proximal and distal parts of the limbs are usually affected symmetrically. Atrophy is much less marked than weakness. Loss of reflexes is found in almost all patients, but may be confined to the ankles. Cranial nerve involvement, sometimes preceding the neuropathy, has been reported infrequently.3;8 CIDP can occur at any age. In the table the sensitivity, specificity, positive likelihood ratio and odds ratios of having CIDP for six important clinical characteristics are given. These figures were derived from a study comparing 23 CIDP patients with 41 patients with an other chronic sensorimotor polyneuropathy.9;10

Table. Sensitivity, specificity, positive likelihood ratio and odds ratios of having CIDP for six important clinical characteristics
Clinical characteristic Sensitivity Specificity Positive LR  OR p-value&
Course with remissions and exacerbations 0.39 0.88 3.21 1.6 0.70
Symmetric sensorimotor polyneuropathy 0.70   0.78 3.17  5.3 0.14
Areflexia 0.52 0.80 2.67 1.3 0.80
increased CSF protein level
> 0.5 g/l 0.87   0.44 1.55 7.7 0.13
> 1 g/l 0.57    0.88 4.63 38.5 0.01
Electrophysiologic investigation consistent with CIDP$ 0.87    0.85 5.94 51.7 0.003
no co-morbidity@ 0.65  0.63 1.78 31.5 0.03
$ modified criteria according to Albers en Kelly11; Three out of four must be present: (i) motor conduction velocities lower than 75% of lower limit of normal in at least one nerve, (ii) distal latenties longer than 130% of the upper limit of normal in at least one nerve, (iii) partial conduction block or abnormal temporal dispersion in at least one nerve segment (> 30% loss of amplitude between proximal and distal stimulation site), (iv) increased f-wave responses of more than 130% of the upper limit of normal in at least one nerve.
@ such as diabetes, alcohol abusus, rheumatoid arthritis, IgG paraproteinemia, history of carcinoma.
& p-value of odds-ratio.
Various diagnostic criteria have been employed. In 1997 a Dutch consensusgroup developed diagnostic criteria for CIDP.12 These criteria are more easily used in clinical practice than the the criteria of the ad hoc subcommittee of the American Academy of Neurology AIDS Task Force 1991 and the criteria of Barohn et al 1989.2;3 Firstly, a nerve biopsy is not mandatory in the new Dutch criteria; secondly, a paraproteinaemia, as long as it is a MGUS, is not considered to be a exclusion criteria for the diagnosis; and finally, the neurophysiological criteria for nerve conduciton slowing and conduction block have been revised according to the latest insights. The AAN criteria were developed in the first place as research criteria and are as such very specific but not very sensitive.


Natural course and prognosis
The prognosis of CIDP is worse than GBS. More than 80 per cent of patients fail to make a spontaneous recovery. There is a need to improve therapy, because CIDP causes prolonged periods of disability and occasionally death. Many patients complaint about fatigue despite relatively normal muscle strength.46

Epidemiology
CIDP can occur at any age. The estimated incidence of CIDP is approximately 0.15/100.000 annually. CIDP is a chronic disorder which causes disability for many years. The prevalence is estimated to be between 1,2 and 1,9/100 000.44;45 These figures will vary depending on the diagnostic criteria used.

Pathophysiology / etiology
Breakdown of myelin, a characteristic of the demyelinating neuropathies, is thought to result from an autoimmune reaction towards nerve components. Since most patients respond well to treatment with high dose intravenous IgG (IVIg) or plasma exchange, circulating autoantibodies are presumably involved in these disorders.22 Yan et al. have shown that passive transfer of demyelination is possible by serum or IgG from CIDP patients, supporting a role for autoantibodies in the pathogenesis of CIDP.23 However, the exact pathogenic nature of the autoimmune response, the identity of autoantigens or mode of action of these treatments remains elusive. Thusfar, no in vitro assays are available to monitor disease activity, allowing adjustment of treatment and prognosis after therapy. Characterization of the autoreactive target epitopes or factors eliciting the autoimmune response is therefore needed. Investigation of inflammatory neuropathy disease mechanisms has mainly focussed on the immune response directed against myelin constituents. Serum antibodies against whole nerve, purified myelin proteins, nerve/myelin-associated integrins and gangliosides have been reported, but whether they cause pathology or arise in response to nerve damage is not clear.24-28 In the rat experimental autoimmune neuritis (EAN) model, disease symptoms similar to GBS and CIDP can be induced by immunization with purified peripheral myelin protein zero (P0), basic protein P2 and peripheral myelin protein 22 kDa (PMP22).29-31 However, the role of antibodies against PMP22 in GBS and CIDP remains a matter of debate since others were not able to replicate findings of Gabriel et al..32-34 Recently, Kwa et al. have also excluded myelin proteins Cx32 and P0 as major target epitopes in GBS and CIDP.34 Yan et al. have described demyelinating anti-P0 antibodies in a subgroup of CIDP patients.25 Mutational analysis of heritable demyelinating neuropathies showed, that aside from myelin proteins, correct expression of non-myelin genes is crucial for myelin synthesis and maintenance as well. These include mutations in the early growth response gene (EGR2/Krox-20), encoding a transcription factor and N-myc downstream-regulated gene 1 (NDRG1), whose function is largely unknown.35-37
Schwann cells play a crucial role in the peripheral nervous system, since they are responsible for production and maintenance of myelin.38;39 An immune attack targeting Schwann cells could therefore affect myelin integrity severely. Immunohistochemical data have suggested involvement of terminal-complement (C5b-9) complex deposition as disease,23;40-42 but the close glial-neural association in the whole nerve or even teased fibre preparations has been hampering the identification of Schwann cell or axonal target epitopes in vivo. Recent data from the neurozintuigen laboratory in Amsterdam combined with recent findings of others suggest that, at least part of the autoimmune reactivity in inflammatory demyelinating neuropathies is not directed against myelin exclusively, but towards non-myelin proteins and epitopes possibly involved in Schwann cell-axon interaction as well.43 Ongoing research integrating further clinical evaluation of prospectively defined patient/serum groups, identification and molecular characterization will be needed to assess the significance of the Schwann cell and neuronal autoreactive epitopes in pathogenesis and clinical course of inflammatory demyelinating polyneuropathies.

Differential diagnosis
CIDP has to be distinguished from Guillain-Barré syndrome (GBS), the inherited demyelinating polyneuropathies, metabolic neuropathies (associated with diabetes, uraemia, acromegaly, hepatitis, amyloidosis, and hypothyroidism), paraneoplastic neuropathies, neuropathies associated with monoclonal gammopathies, neuropathies associated with human immunodeficiency virus or Lyme’s disease, and multifocal motor neuropathy. Lewis and Sumner have described patients with a multifocal sensorimotor demyelinating polyneuropathy but this disorder should probably be considered as a variant of CIDP.13;14 CIDP is often considered to be a chronic variant of GBS. Differentiation of the two disorders relies on arbitrary clinical criteria of the time necessary to reach maximum deficit. In GBS this is less than 4 weeks and in CIDP more than 8 weeks.2;5 A subacute idiopathic demyelinating polyradiculopathy has been described with a monophasic illness during 4 to 8 weeks providing a link between GBS and CIDP.15 It is important to distinguish these patients from real CIDP patients as approximately half of them will recover spontaneously and the remainder respond very well to steroids. CIDP can start as an acute demyelinating polyneuropathy and then will be indistinguishable from GBS. However the course of the disease will reveal the correct diagnosis in the end. The distinction between CIDP and GBS is important because the course, treatment and outcome are different.16;17

Table. Differential diagnosis of CIDP18 
Chronic idiopathic axonal polyneuropathy (CIAP)
Hereditary motor and sensory neuropathy type I
X-linked hereditary motor and sensory neuropathy
Hereditary liability to pressure neuropathy
Polyneuropathy with monoclonal gammopathy of undetermined significance (MGUS)
POEMS syndrome
X adrenoleucodystrofy
Amiodarone (cordarone) polyneuropathy
Motor neuron disease or MMN
Hypothyroidism associated polyneuropathy
Non-systemic vasculitis neuropathy
 

Ancillary investigations
The diagnosis of CIDP is based on the clinical, electrophysiological, cerebrospinal fluid features and, to a limited degree, on histopathology. Cerebrospinal fluid protein levels are generally elevated without cellular reaction.4 Electrophysiologically, the disease is characterised by reduced nerve conduction velocities, abnormal temporal dispersion and conduction block.3;19;20 The pathological findings include multifocal demyelination, mononuclear cells in close approximation to demyelinated axons, remyelination, fibre loss and only sometimes 'onion bulbs'.3;4 Lymphocytic infiltration can be found in sural nerve biopsies, but, as may be expected from a predominantly motor neuropathy with multifocal involvement, biopsies are frequently normal and in general not necessary to make the diagnosis.9;21

Therapy

A beneficial effect of immunosuppressive therapy (e.g. corticosteroids) and plasma exchange has been demonstrated in randomised clinical trials.47-53 Several uncontrolled studies have suggested a beneficial effect of intravenous immunoglobulin.19;20;54-57 As a result, a number of randomised trials with IVIg in CIDP have been undertaken.58-63 The efficacy and safety of intravenous immunoglobulin (IVIg) in CIDP has been reviewed and compared with plasma exchange and prednisolone in a Cochrane systematic review.64;65
Six randomised controlled trials were considered eligible for review including 170 patients.58-63 Four studies on 113 patients compared intravenous immunoglobulin against placebo.59;61-63 One trial with 17 patients compared intravenous immunoglobulin with plasma exchange in a cross-over design and one trial compared intravenous immunoglobulin with prednisolone in 32 patients.58;60

IVIg versus placebo59;61-63
A significantly higher proportion of patients improved in disability within one month after the onset of intravenous immunoglobulin treatment as compared with placebo (relative risk 3.17, 95% confidence interval 1.74 to 5.75). The chance for CIDP patients to improve spontanously is approximately 15%. Treatment with IVIg increased patient ‘s chance of improvement to 47%. The absolute risk difference is thus 32% which gives a number needed to treat of 3. In other words, if treated with IVIg one in every three patient will improve due to this treatment. However, if ten patients are treated with IVIg, three will improve due to the therapy, but approximately two patients will improve spontaneously and five patients will not improve and need additional treatment. Long-term IVIg treatment has not been investigated.

IVIg versus plasma exchange 58
The effect size for change of mean disability score at six weeks comparing intravenous immunoglobulin with plasma exchange revealed no difference between the two therapies (effect size -0.07, 95% confidence interval -0.76 to 0.63.)

IVIg versus prednisolone 60
The proportion of patients with a significant improvement did not differ significantly between prednisolone and intravenous immunoglobulin (relative risk of 0.91 (95% CI 0.50 to 1.68). Also, no difference in mean improvement on the disability scale was found at two weeks (effect size -0.12, 95% confidence interval -0.68 to 0.45) or six weeks (effect size -0.07, 95% confidence interval -0.63 to 0.50) between prednisolone and intravenous immunoglobulin.

Side effects
In the Cochrane review65, mild and transient side effects were reported in 38 out of 99 (38%) IVIg treated patients, in nine out of 46 (20%) placebo treated patients, and in 11 out of 27 (41%) prednisolone treated patients. Serious side effects (aseptic meningitis (1), transient hypertension (3), and heart failure (1)) were encountered in 5 out of 99 (5%) IVIg treated patients, in two out of 46 (4%) placebo treated patients, in two out of 27 (7%) prednisolone treated patients and in two out of 17 (12%) PE patients. These differences were not statistically significant. In the IVIg versus placebo trials, the relative risk for the development of a serious side effect was 1.43 (95% CI 0.33 to 6.17), indicating an insignificant and very small increased risk with IVIg treatment. Considering all side effects did not change this risk estimate (relative risk 1.6, 95% CI 0.91 to 2.79). In the IVIg versus prednisolone trial, the relative risk of developing a serious adverse event was 0.45 (95% CI 0.04 to 4.69). The relative risk of all side effects was 1.47 (95% CI 0.86 to 2.53) which was not significant. Thus, in comparison with plasma exchange and prednisolone there were no differences in the occurrence of minor or major side effects. However, it should be noted that the number of PE treated patients was small compared to the number of IVIg treated patients. Furthermore, serious side effects known to occur after prolonged treatment with steroids were not seen due to the very short prednisolone regimen given in this particular trial.

Initial treatment
Since IVIg, plasma exchange and prednisolone seem to be equally effective in the treatment of patients with CIDP, it is currently uncertain which of these should be the first choice. Many consider prednisolone as the mainstay of therapy in CIDP patients probably because of its ease of administration and the low costs.51;66 However, the choice of first line treatment should be made depending on several factors.
Firstly, disease severity: patients with very mild symptoms and signs which not or only slightly interfere with activities of daily living can be monitored without treatment. In these cases the chance of treatment induced adverse events do not weigh against the possible small gain in impairment and disability. Patients with moderate to severe impairment and disability, e.g. when hospitalisation is required or ambulation is severely impaired, can better be started on IVIg, 2 gram/kg over 2 or 5 days, as rapid improvement is desired.
Secondly, contra-indications for and side effects of long-term steroid therapy should be considered.
Thirdly, patients with a pure motor form of CIDP have been reported to deteriorate on steroid treatment.67 In these patients IVIg treatment should be first choice and if started on prednisolone patients should be monitored very closely for deterioration.
Patients with mild to moderate impairment and disability, not having a pure motor form of CIDP and without contraindications for steroid therapy, can be started on prednisolone 0.5 – 1.0 mg/kg with a maximum of 60 mg daily.
Plasma exchange is complicated, expensive and has no advantages over immunoglobulin treatment, but depending on local availability plasma exchange can be used instead of IVIg. It should be kept in mind that plasma exchange alone is seldom sufficient and additional treatment with immunosuppressive therapy is necessary to reduce the need for repeated plasma exchanges.

Maintenance treatment
Information on exact treatment protocols, e.g. dose, taper regime, frequency of administration, combination of treatment is incomplete. The next section is largely based on our interpretation of the literature and personal experience.
Patients started on prednisolone should be continued for 4 to 8 weeks on their starting dose and then very slowly tapered to maintenance dose over a period of one to two years. Up to 70 per cent of patients relapse when the dose of prednisolone is reduced.66;68;69  A relapse during tapering is treated by a dose of prednisolone just above the dose at which the patient had stable disease. Depending on how active the disease is, an immunosuppressive drug can be added to the prednisolone treatment, as these medications have a steroid-sparing effect. Only azathioprine has been investigated in a controlled trial and found not to be effective.70 However, the trial duration was not long enough to exclude that azathioprine had a beneficial effect. No controlled trials are available for the other immunosuppressive drugs. The merits of immunosuppressants and other immunomodulatory agents as adjuvant therapy are the subject of a current systematic review.71
If patients started on IVIg, improve, a wait and see policy should be implemented. Approximately one third of patients will not need further treatment.20;69;72  Patients with a secondary deterioration can be treated with a second course of IVIg and can immediately afterwards be started on prednisolone 0.5 – 1.0 mg/kg with a maximum of 60 mg to maintain the improvement induced by IVIg. Patients with contraindications for steroid therapy (or if other reasons preclude corticosteroid therapy), can be maintained on a regular scheme of IVIg: 0.4  gram/kg for 1 day every 2 tot 4 weeks. If patients become stably improved the dose of IVIg should be reduced first before the frequency of administration is lowered.69 Depending on how active the disease is, an immunosuppressive drug can be added to the IVIg treatment, as these medications have a IVIg-sparing effect. Patients who fail to respond to the initial treatment with prednisolone should be switched to IVIg and vice versa. Plasma exchange can be useful in patients who do not respond to prednisolone or IVIg. Approximately 10-15% of patients fail to respond to these treatments and various other immunosuppressive drugs are used to induce improvement, such as cyclosporine,73 cyclophosphamide74;75,  interferon76;77,  rituximab78, or mycophenolate mofetil.79 No randomised clinical trials are available to support this treatment. Some of these patients will not respond to any therapy probably because of severe secondary axonal involvement which takes years to improve.

When to stop?
CIDP is a chronic disease which can run a chronic progressive, relapsing-remitting or monophasic course. No evidence-based guidelines can be given as none of the trials systematically assessed patients at three months or assessed whether long lasting remission occurred. However, it is reasonable to try to taper prednisolone therapy to a very low dose in approximately one to two years. If a patient remains stable for an extended period, e.g. 6 months on a dose of 5 mg per day, it is considered worthwhile to try to discontinue the treatment. Side effects are of influence on the individual tapering scheme and should be taken into account.
In patients who are stable on a regular scheme of IVIg, the dose of IVIg should be reduced sufficiently and the frequency should be brought back to at least once every 4 weeks before an attempt is made to discontinue treatment. Recent results suggest that the addition of an immunomodulatory drug, or a switch to another treatment modality seems especially worthwhile in patients who are still on IVIg treatment one to two years after onset of IVIg, because the chance to go into a long-term remission with IVIg therapy only seems to be low. (P.A. van Doorn, personal communications). Nevertheless, it is worthwhile to discontinue IVIg treatment once in a while and wait until a patients start to deteriorate before administration of a new gift of IVIg. In this way patients in a long-term remission will be detected.


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