Original Paper Received: December 19, 2014 Accepted: March 15, 2015 Published online: April 29, 2015
Eur Neurol 2015;73:294–302 DOI: 10.1159/000381767
Natalizumab as a Disease-Modifying Therapy in Chronic Inflammatory Demyelinating Polyneuropathy – A Report of Three Cases Jean-Michel Vallat a Stéphane Mathis b Karima Ghorab a Michel-André Milor a Laurence Richard a Laurent Magy a
a
Department of Neurology, National Referral Center for ‘Rare Peripheral Neuropathies’, University Hospital Limoges, Limoges, and b Department of Neurology, University Hospital Poitiers, Poitiers, France
Abstract Background: Several treatments are available to treat the immune-mediated chronic inflammatory demyelinating polyneuropathy (CIDP). Among these treatments, intravenous immunoglobulins, corticosteroids and plasma exchanges are validated and widely used. A few immunosuppressive drugs have been tried, but they had little efficiency. Methods: We describe three CIDP patients treated by Natalizumab (acting against cellular adhesion and T-cell migration) after a failure of the validated treatments. Results: We observed a long-term improvement in one patient, a dramatic improvement over a significant duration in another patient and stabilization in the last one. Conclusion: This open label study provides evidence for the value of Natalizumab as second-line treatment for individual patients with a high dependency on waning efficacy of first-line therapies. CIDP is characterized by heterogeneity of clinical phenotypes, electrophysiological and pathological features, and various variable courses types of evolution. The different responses to drugs of our patients are consistent with some reported cases and may reflect the spectrum of lesional mechanisms and the molecular dysfunctions in CIDP. © 2015 S. Karger AG, Basel
© 2015 S. Karger AG, Basel 0014–3022/15/0736–0294$39.50/0 E-Mail [email protected] www.karger.com/ene
Introduction
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated neuropathy involving cellular and humoral immunity. It is clinically heterogeneous and generally symmetric sensorimotor neuropathy evolving as a monophasic, relapsing or progressive, disorder [1]. The current approach to treat this neuropathy is a suppression of autoimmune responses; intravenous immunoglobulins (IVIg), corticosteroids and plasma exchange have proven their efficacy and are used in the short and long terms [2]. The response to IVIg and plasma exchange supports a role for humoral factors and autoantibodies in CIDP [3], also provided by the presence of immunoglobulin G and complement in sural nerve biopsies [4]. Some axoglial antigens have been proposed as candidate antigens in a few CIDP patients [5]. In addition to these mechanisms, biological and histopathologic findings suggest that T cells play a key role in the pathogenesis of this disorder. The efficacy of immunosuppressants in CIDP has been suggested by some studies [6–8], but randomized controlled trials have failed to show any effect of immunosuppressants to date [9–11]. Other drugs have been used to treat patients with CIDP in a few series [12]. Some of these drugs act by selectively suppressing T cells (Alemtuzumab), B cells (Rituximab) or complement (Eculizumab), with various clinical efficacies [13]. Prof. Jean-Michel Vallat Department of Neurology, National Referral Center for ‘Rare Peripheral Neuropathies’ University Hospital Limoges, 2 Avenue Martin-Luther-King FR–87042 Limoges Cedex (France) E-Mail jean-michel.vallat @ unilim.fr
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Key Words Natalizumab · CIDP · Immune-mediated neuropathy · VLA4 · VCAM1 · Blood-nerve barrier
ONLS 12 11 10 9 8 7 6 5 4 3 2 1 0
Patient 1 0
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24
36
48
60
72
84
96
108
120
132
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Duration (months) ONLS 12 11 10 9 8 7 6 5 4 3 2 1 0
Patient 2 0
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36
48
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72
84
96
108
120
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Duration (months)
ONLS 12 11 10 9 8 7 6 5 4 3 2 1 0
Patient 3 0
12
24
36
48
60
72
84
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Duration (months) Natalizumab (monthly) Natalizumab (quarterly)
Oral corticosteroids
Infusion on intravenous immunoglobulins (0.4 g/kg/day during five days)
Subcutaneous immunoglobulins (weekly)
ENMG
Fig. 1. Course of CIDP (evaluation with total ONLS) for our three patients (with treatments used for each one). For patient 1, we observe a long-term improvement; for patient 2, the worsening tends to reverse (with relapse after each stopping of Natalizumab); for patient 3, slowly worsening and then stabilization was observed.
Natalizumab in CIDP
Observations
Informed consent was obtained from each patient after having explained the rationale of using Natalizumab in CIDP (but that it had not been validated as an efficient treatment in this indication) and its potential adverse effects. The clinical course of the disease (evaluated with the Total Overall Neuropathy Limitations Scale, or total ONLS) [15] and the use of Natalizumab (and other therapeutics) are shown in figure 1: the total duration of folEur Neurol 2015;73:294–302 DOI: 10.1159/000381767
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Among these alternative drugs, Natalizumab (used in the treatment of multiple sclerosis), acting against cellular adhesion and T-cell migration (by acting directly on the α4β1-integrin (also known as ‘very late antigen-4’ or VLA4) on leukocytes), might be a promising treatment for some immune-mediated neuropathies, even though it was found to be ineffective in one case of CIDP [14]. According to this rationale, we used Natalizumab in three patients with CIDP who presented very severe and frequent recurrent relapses over a number of years.
Patient 1 This 68-year-old woman (with a medical history of arterial hypertension and depression) was admitted to hospital for distal numbness in her upper limbs for a few months, before complaining of the same symptoms in her lower limbs, accompanied with gait ataxia and absent deep tendon reflexes (without weakness): the total ONLS score was 5/12 after 10 months. Electrophysiological findings were consistent with a demyelinating sensorimotor polyneuropathy (motor nerve conduction in upper limbs was 25–38 m/s, with increase of distal latencies) without severe active distal denervation in the lower limbs (presence of slight fibrillation in the tibialis anterior muscles) (table 1). The clinical and electrodiagnostic findings were consistent with the diagnosis of CIDP according to the EFNS/PNS criteria [2]. Laboratory tests only showed a serum IgG-kappa monoclonal gammopathy; no plasma cell expansion was found on bone marrow aspiration. The other ancillary tests were normal. AntiMAG and other anti-ganglioside (GM1, asialo-GM1, GM2, GD1a, GD1b, and GQ1b) antibodies were negative in the serum. Cerebrospinal fluid protein (CSF) content was elevated (88 mg/dl), without cells. On a sural nerve biopsy (performed at the age of 68 because of the rapid worsening), microscopical examination was in favor of CIDP: some T cells in the perineurium and a discrete loss of myelinated fibers (fig. 2) with features of a demyelinating process (with abnormally thinned myelin sheaths) were observed; the density of myelinated nerve fibers was 6,503/mm2 (7,618/mm2 for a normal control of the same age); by electron microscopy, we observed a variable degree of Schwann cell proliferations (‘onion bulb’ formations) around de- and re-myelinating fibers, but no abnormal deposits in the endoneurium. Direct immunofluorescence (frozen sections) did not show any abnormal deposits (fig. 2). Because of the severity of the sensory ataxia (causing substantial disability), regular and effective courses of IVIg were decided, albeit requiring periodic infusions. After 2 years, we observed an improvement with a total ONLS score at 2/12 (but with recurrent relapses each month) before observing a dramatic progressive worsening during the next year (total ONLS score was 8/12). At that time, oral prednisolone (at a daily dose of 60 mg) was given for 3 months, without any substantial improvement. So, 4 years after the beginning of the symptoms, 296
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perfusions of Natalizumab (13 monthly infusions, then six quarterly infusions) were added to IVIg. After 12 months of this combination, the patient presented a dramatic improvement of her sensory ataxia (without any relapse). She is now still fully ambulatory and has an almost complete disappearance of her numbness in the four limbs. Twenty-seven months after the beginning of Natalizumab, the total ONLS score was still 2/12 (1/12 one year later, 0/12 after six other months then stable). After 19 perfusions (fig. 1), Natalizumab was stopped because of the positivity of the JC virus serology (normal brain MRI). No IVIg treatment was needed after more than 60 months; 12 months after Natalizumab had been stopped, the electrophysiological study showed a mild decrease of motor distal latencies (except for the right tibial nerve) and a mild increase in CMAP amplitudes in all four limbs, but with a mild decrease of the motor NCV as well (table 1). Patient 2 A 70-year-old woman, with a medical history of cataract and basocellular carcinoma, complained of distal paresthesias in her lower limbs, and a few months later in her upper limbs (with bilateral attitude tremor in the upper limbs). After 8 months, she presented mild gait disturbance, without any motor deficit and general areflexia (total ONLS score: 4/12). Ten months later, nerve conduction studies were performed and showed a severe mainly distal sensorimotor demyelinating polyneuropathy with increased motor distal latencies and decreased motor nerve conduction velocities (NCVs) in the four limbs, also with some conduction blocks; no sensory nerve action potentials (SNAP) were recorded in all four limbs (table 1). CSF protein concentration was 33 mg/dl, without cells. Other ancillary tests ruled out other causes of peripheral neuropathy. As for the two other patients, there were no anti-MAG or other anti-ganglioside (GM1, asialo-GM1, GM2, GD1a, GD1b, and GQ1b) antibodies in the serum. The clinical and laboratory findings were judged consistent with the diagnosis of CIDP according to the EFNS/PNS criteria [2]. A treatment by IVIg was initiated because the patient was considered to have a significant disability caused by sensory ataxia and prominent tremor of both hands. Because of side effects after the second IVIg infusion (urticaria), the patient was treated by oral corticosteroids (1 mg/kg/day). No improvement was observed although there was a stabilization; it was decided to decrease slowly and then to stop steroids after 14 months. After this period, a treatment by subcutaneous immunoglobulins Vallat/Mathis/Ghorab/Milor/Richard/ Magy
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low-up of these patients (since the onset of symptoms) was 108 months for patient 1, 129 months for patient 2 and 160 months for patient 3.
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297
lower limbs
upper limbs
lower limbs
upper limbs
Sensory study
Motor study
upper limbs
lower limbs
upper limbs
Before Natalizumab
Sensory study
Motor study
First ENMG
right left right left
radial nerve
right left
tibial nerve
median nerve
right left
right left
ulnar nerve
peroneal nerve
right left
right left
superficial peroneal nerve
median nerve
right left
right left
radial nerve
sural nerve
right left
median nerve
right left
tibial nerve
– ND
ND ND
18 ms –
25.1 ms 14.2 ms
3.88 ms ND
6.62 ms ND
– ND
2.1 ms 1.6 ms
– 1.5 ms
– ND
3.7 ms 5.5 ms
4.3 ms 4.2 ms
left right left
2.7 ms
right
ulnar nerve
peroneal nerve
4.2 ms
right left
median nerve
16.2 ms 3.8 ms
0 μV ND
ND ND
0.11 mV –
0.07 mV 0.91 mV
6 mV ND
4.4 mV ND
0 μV ND
11 μV 17 μV
0 μV 2.1 μV
0 μV ND
3.1 mV 4.0 mV
5.0 mV 5.8 mV
6.2 mV*
2.3 mV*
0.7 mV 3.1 mV*
– ND
ND ND
15.5 m/s –
27.4 m/s 18.8 m/s
16.6 m/s ND
20.9 m/s ND
– ND
44.3 m/s 40.1 m/s
– 49.3 m/s
– ND
37.5 m/s 40.8 m/s
39.3 m/s 41.5 m/s
37.9 m/s
35.3 m/s
25 m/s 31.6 m/s
NA NA
NA NA
– –
– –
– ND
– ND
NA NA
NA NA
NA NA
NA NA
71.3 ms ND
– –
–
55.1 ms
– –
ND ND
ND –
17.2 ms 12.7 ms
7.2 ms 6.8 ms
ND 6.1 ms
ND 7.3 ms
– –
– –
– –
– –
– –
13.2 ms 20.3 ms
12.7 ms
8.6 ms
13.1 ms 23.7 ms
distal latency
F wave
distal latency
distal conduction amplitude velocity
Patient 2
Patient 1
ND ND
ND 0 μV
0.5 mV 0.6 mV
1 mV 1.3 mV
ND 4 mV
ND 3.6 mV
0 μV –
0 μV 0 μV
0 μV 0 μV
0 μV 0 μV
0 mV 0 mV
0.3 mV* 0.2 mV
1.3 mV
1.7 mV
1.5 mV 1.1 mV
distal amplitude
ND ND
ND –
10.1 m/s ND
17 m/s 21.1 m/s
ND 16.6 m/s
ND 18.9 m/s
– –
– –
– –
– –
– –
19.3 m/s 20 m/s
27.5 m/s
30.6 m/s
20.3 m/s 22 m/s
conduction velocity
Table 1. Electrophysiological study of motor and sensory nerves, before and after treatment with Natalizumab
NA NA
NA NA
– –
– –
ND 55.8 ms
ND 72.5 ms
NA NA
NA NA
NA NA
NA NA
– –
– –
–
–
– 62.5 ms
F wave
ND ND
– –
ND ND
– –
ND ND
– –
– –
ND ND
ND ND
– –
ND ND
– –
ND
ND
21.0 ms 17.7 ms
distal latency
Patient 3
ND ND
0 μV 0 μV
ND ND
0 mV 0 mV
ND ND
0 mV 0 mV
0 μV 0 μV
ND ND
ND ND
0 μV 0 μV
ND ND
0 mV 0 mV
ND
ND
1.4 mV 0.1 mV*
distal amplitude
ND ND
– –
ND ND
– –
ND ND
– –
– –
ND ND
ND ND
– –
ND ND
– –
ND
ND
41 m/s 42 m/s
conduction velocity
NA NA
NA NA
NA NA
NA NA
NA NA
NA NA
ND ND
– –
ND
ND
– –
F wave
298
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Vallat/Mathis/Ghorab/Milor/Richard/ Magy
lower limbs
upper limbs
right left
right left
lower sural limbs nerve
superficial peroneal nerve
right left
radial nerve
right left
right left
tibial nerve
upper median limbs nerve
right left
right left
ulnar nerve
peroneal nerve
right left
right left
right left
median nerve
superficial peroneal nerve
sural nerve
ND ND
ND ND
2.08 ms ND
ND ND
10.9 ms ND
8.55 ms ND
3.11 ms ND
4.35 ms ND
ND ND
– –
ND ND
ND ND
11.7 μV ND
ND ND
0.85 mV ND
0.37 mV 2.2 mV*
7.4 mV* ND
4.6 mV ND
ND ND
0 μV 0 μV
ND ND
ND ND
– ND
ND ND
21.6 m/s ND
25.3 m/s 24.9 m/s
34.2 m/s ND
29 m/s ND
ND ND
– –
NA NA
NA NA
NA NA
NA NA
– ND
– –
44.7 ms ND
44.3 ms ND
NA NA
NA NA
ND ND
2.7 ms ND
ND –
ND ND
5.9 ms ND
3.8 ms ND
ND 5.2 ms
ND 8.2 ms
ND ND
– ND
distal latency
F wave
distal latency
distal conduction amplitude velocity
Patient 2
Patient 1
ND ND
2.5 μV ND
ND –
ND ND
1.1 mV ND
2.5 mV ND
ND 6.2 mV
ND 4.4 mV
ND ND
0 μV ND
distal amplitude
ND ND
28.1 m/s ND
ND –
ND ND
19.4 m/s ND
25.3 m/s ND
ND 23 m/s
ND 21.4 m/s
ND ND
– ND
conduction velocity
NA NA
NA NA
NA NA
NA NA
– ND
83.8 ms ND
ND 66.3 ms
ND 65.3 ms
NA NA
NA NA
F wave
– –
ND ND
ND ND
– –
ND ND
– –
ND ND
– –
– –
ND ND
distal latency
Patient 3
* Conduction block. NA = Not applicable; ND = no data; – = not obtainable. The time of each electrophysiological study is presented in figure 1.
Sensory study
After Natalizumab
Motor study
lower limbs
Table 1. (continued)
0 μV 0 μV
ND ND
ND ND
0 μV 0 μV
ND ND
0 mV 0 mV
ND ND
0 mV 0 mV
0 μV 0 μV
ND ND
distal amplitude
– –
ND ND
ND ND
– –
ND ND
– –
ND ND
– –
– –
ND ND
conduction velocity
NA NA
NA NA
NA NA
NA NA
NA NA
NA NA
F wave
Patient 3 A 34-year-old woman developed subacute distal paresthesias in her four limbs within 12 weeks. One year later, she presented a mild distal weakness of the lower limbs (Medical Research Council: grade 4 on the tibialis anterior muscles) with also a mild gait disturbance, distal hypoesthesia of the lower limbs and generalized areflexia (total ONLS score: 2/12). Nerve conduction studies showed a severe sensorimotor demyelinating polyneuNatalizumab in CIDP
Fig. 2. Sural nerve biopsy (electron microscopy section) of patient
1 showing too thin myelin sheath.
ropathy, with axonal loss in the lower limbs (no CMAP and SNAP) and some conduction blocks in the upper limbs; most of the nerves (particularly in the lower limbs) were not excitable (table 1). The ancillary tests ruled out another cause of peripheral neuropathy. There were no anti-MAG or anti-ganglioside antibodies (GM1, asialoGM1, GM2, GD1a, GD1b, and GQ1b) in the serum. An elevated protein level was observed in the CSF (110 mg/ dl), without cells. On a sural nerve biopsy (performed at the age of 36), we observed a significance loss of myelinated fibers with features of a demyelinating process, with thin myelin sheaths and by electron microscopy a variable degree of Schwann cell proliferations (‘onion bulb’ formations). Numerous axons had lost their myelin sheaths; the density of myelinated fibers was 2,881/mm2 (9,604/mm2 for a normal control of the same age). Overall, the clinical and laboratory findings were consistent with the diagnosis of CIDP according to the EFNS/PNS criteria [2]. We have previously presented some details of this patient (case 8 of Vallat et al. [16]). For the next 9 years, we first observed the stabilization with IVIg (one course every one, 2 or 3 months) before she developed a slowly progressive worsening (regular IVIg treatment did not induce any significant improvement at that time). After 10 years, multiple hypertrophic peripheral nerves were clinically palpable; at that time, a lumbar MRI was performed and showed an important hypertrophy of the nerve roots (fig. 3). Three years later, the total ONLS score was 6/12, and Natalizumab was begun because the patient was considered no longer responsive to IVIg: after 11 courses of monthly treatment (while Eur Neurol 2015;73:294–302 DOI: 10.1159/000381767
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(SCIg) was prescribed for 2 years: there was no improvement during the first year (total ONLS score was 4/12). Over the following year, the total ONLS score increased to 7/12 because of distal weakness of the lower limbs; furthermore, she again presented a severe attitude tremor of her upper limbs (without cerebellar symptoms or parkinsonism), with fluctuations depending of the course of the CIDP. Another treatment by IVIg (with a different trademark) was tried, without any side effect at this time. The patient’s state improved markedly, but she needed periodic infusions of IVIg (fig. 1). The electrophysiological study showed a decrease of motor distal latencies (except for the right tibial nerve) and a mild increase in CMAP in all four limbs; a decrease in the motor NCV and still no SNAP in the four limbs were also observed (table 1). After 1 year, because of a lack of improvement, we decided to add a monthly treatment with Natalizumab while continuing IVIg (one course every 2 months). The total ONLS score decreased slightly (5/12) after 11 monthly infusions of Natalizumab, and the frequency of IVIg infusions could be decreased (one every 4 months). After having stopped Natalizumab, the patient was stable for 5 months before an increase of tremor during three weeks; then a subacute worsening of gait disturbance happened (total ONLS: 7/12). Six months after having stopped Natalizumab, 8 monthly infusions of Natalizumab were prescribed again: a dramatic improvement with a disappearance of tremor and of gait ataxia (total ONLS: 3/12) was observed. At that time, because of a positiveness of the JC virus serology (but with normal brain MRI), Natalizumab was stopped again and CIDP symptoms and signs were stable for 6 months (total ONLS: 3/12); then, spontaneously, a subacute worsening appeared during the next month: total ONLS increased to 5/12 (with a stabilization during 5 months), then the total ONLS decreased 19 months after the end of the second course of Natalizumab (3/5) (fig. 1). The last ENMG (few weeks after the end of the second course of Natalizumab) showed an improvement in motor conduction velocities and amplitude in the four limbs (table 1).
Fig. 3. Lumbar MRI (coronal plane) showa
continuing IVIg), no significant clinical and/or electrophysiological improvement was observed, but a stabilization of the total ONLS score (6/12) one year after the end of the 12 monthly infusions of Natalizumab (fig. 1). Natalizumab was stopped because of a positivity of the JC virus serology (normal brain MRI). No adverse effect of Natalizumab (except regressive urticaria after the second course) was reported by the patient. After the end of Natalizumab treatment, the electrophysiological study showed no motor or sensory improvement in the four limbs (table 1). Finally, after about 14 years of evolution, we decided to stop IVIg and to propose plasma exchanges.
Discussion
Corticosteroids, plasma exchange (PE) and intravenous immunoglobulins (IVIg) are effective and are recommended to treat CIDP [2]; nevertheless, the ways in which these treatments act are not fully understood, in part because the mechanisms causing nerve damage in CIDP are themselves not completely known [1]. Because usual treatments of CIDP are not always effective and because some patients are highly dependent on high-dose IVIg or steroids, there is a need to find alternative treatments that may act as disease-modifying therapies. In this report, we have presented three patients with a severe sensory ataxic form of CIDP who had a clear benefit from adding Natalizumab to their usual treatment regimen. The term CIDP includes a remarkably heterogeneous group of phenotypes with different clinical courses, 300
Eur Neurol 2015;73:294–302 DOI: 10.1159/000381767
b
atypical variants, and sometimes the presence of a monoclonal gammopathy [17]. Underlying such variability, there is probably also a broad spectrum of immune events and molecular mechanisms that might explain the heterogeneity of response to treatments. Various immunosuppressants have been reported as being efficient in isolated cases [8, 18]; nevertheless, randomized control trials (RCT) of most of these drugs have failed to show any evidence of efficacy [9, 11]. Again, these discrepancies may stress the heterogeneity and complexity of mechanisms in CIDP. Recently, the presence of antibodies against conformational epitopes of the CNTN1/CASPR1 complex was confirmed in a subset of CIDP patients with similar clinical features such as higher age at onset, predominant motor symptoms, rapidly progressive course and partial or inexistent response to IVIg [5]. Finally, the benefits of recommended treatments (IVIg, steroids and PE) may be absent, inadequate or short-lived (lasting a few weeks) in some patients [11], so that alternative treatments have to be tried in reference centers. Some reports have shown that the pathological breakdown of the blood nerve barrier (BNB) (so that the nerve parenchyma is infiltrated by T cells and a variety of molecules such as immunoglobulins, cytokines and chemokines) is an important mechanism in the disease process of several types of dysimmune neuropathies [19]. Moreover, morphological abnormalities of endothelial cells and pathological changes of endoneurial microvessels (due to the alteration of tight junction proteins between endothelial cells) can be observed in some dysimmune neuropathies [20]. Vallat/Mathis/Ghorab/Milor/Richard/ Magy
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ing hypertrophy of the lumbar roots (arrows) on T1-weighted (a) and T2-weighted (b) sequences.
Natalizumab is a recombinant humanized α4-integrin monoclonal antibody originally derived from a murine antibody against α4-integrin, which belongs to the large family of adhesion receptors of the integrin family; it mediates both cell-extracellular matrix and cell-cell interactions [21]. The major endothelial ligand for α4-integrin is vascular cell adhesion molecule-1 (VCAM-1) that is upregulated on endothelial cells during inflammation. In consequence, Natalizumab appears to both prevent the recruitment of immune cells into inflamed tissue (by blocking the binding of α4-integrin to VCAM-1) and suppress the ongoing inflammatory activity (by interrupting the interaction between α4-integrin-expressing leukocytes and extracellular matrix proteins, such as fibronectin and osteopontin) [22]. In 1991, Yednock et al. first demonstrated that targeting α4-integrin could prevent the development of demyelinating lesions in a mouse model of multiple sclerosis (MS) [23]. So, Natalizumab was initially tried in chronic inflammatory diseases of the central nervous system, and it is now approved for the treatment of relapsing-remitting MS since 2004. Even if it is not fully understood, it is known that VLA4 and VCAM-1 participate in the pathogenesis of inflammatory diseases of the peripheral nervous system [24]. The experimental immunological blockade of VCAM-1 can reduce damage on peripheral nerve myelin (in animals with experimental autoimmune neuritis), but without offering a total protection for the nerve [25]. Recently, T cells expressing α4-integrin were demonstrated in the peripheral nerve of a CIDP patient [14]. However, despite a good targeting of T cells by Natalizumab, no positive clinical response was observed for this patient with a highly active form of CIDP. One of our three cases (patient 1) dramatically improved under Natalizumab treatment (13 monthly, then 6 quarterly courses), with long-term stabilization and definitive interruption of IVIg infusions; in that case, we envisage the progressive decrease of the dose of Natalizumab. Our patient 2 also improved after Natalizumab; a subacute relapse appeared 6 months after this treatment was interrupted; Natalizumab was tried again but finally stopped because of JC virus positivity, leading to a new relapse of the disease. In that case, and as for MS [26], we wondered if this severe relapse might have been due to the interruption of Natalizumab. For patient 3, the course of the disease was slowly progressive: Natalizumab apparently stopped the worsening, and the total ONLS score (6/12) seems to have been stabilized; considering this last patient, it has to be stressed that Natalizumab has been prescribed after 13 years (with severe axonal loss), so that significant clini-
cally palpable nerve lesions and on a lumbar MRI presence of a significant (an important) and diffuse hypertrophy of the root nerves were observed, as for the case of Wolf et al. [14]. It is known that axonal loss, correlated with a higher disability and a worst response to treatments, is the major long-term prognostic factor of CIDP [27]. These data suggest that the efficiency of Natalizumab may be correlated with the extent of the axonal loss. Moreover, it is also possible that nerve root hypertrophy, reflecting a chronic neuropathic process, may be a predictive factor of inefficiency of Natalizumab in CIDP. Finally, these variable responses to Natalizumab observed in our three patients might well reflect the heterogeneity of lesion mechanisms in CIDP. Although Natalizumab has been shown to be effective in MS and Crohn’s disease, there are concerns that some patients may develop progressive multifocal leukoencephalopathy (PML) under this treatment; risk factors for this rare side effect are duration of treatment (more than 24 infusions), previous treatment with immunosuppressants and a positive serodiagnosis test for JC virus [28]. Indeed, PML is caused by a reactivation of JC virus in the brain and this does not require blood-brain-barrier breakdown, as it has been described in a patient with Crohn’s disease [29]. It would therefore be reasonable to test for anti-JC virus antibodies before treating patients with Natalizumab, and exclude patients with a positive serodiagnostic test, unless no other alternative treatment is available. In conclusion, CIDP is an immune-mediated neuropathy that can usually be treated with IVIg, corticosteroids and plasma exchanges. However, probably because of the heterogeneity of the disease, an inadequate response to these first-line treatments is sometimes observed. In such patients, because of the BNB alteration in immune-mediated neuropathies, Natalizumab could be proposed as a second line of treatment. As such, severe CIDP cases are not very common and also because some of these cases might not respond to Natalizumab, it does not seem realistic to propose randomized controlled trials (RCT). In a first step, the use of Natalizumab could be considered on a case by case basis for patients who have not responded to treatments validated by RCT. More detailed and specific indications of Natalizumab might be determined after we find out more about the molecular dysfunction(s) in each case.
Natalizumab in CIDP
Eur Neurol 2015;73:294–302 DOI: 10.1159/000381767
Disclosure Statement
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The authors declare that they have no conflict of interest.
References
302
11
12
13
14
15
16
17
18
19
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sone in chronic inflammatory-demyelinating polyneuropathy. Neurology 1985; 35: 1173– 1176. Mahdi-Rogers M, Swan AV, van Doorn PA, Hughes RA: Immunomodulatory treatment other than corticosteroids, immunoglobulin and plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev 2010; 11: CD003280. Magy L, Mathis S, Vallat JM: Diagnostic and therapeutic challenges in chronic inflammatory demyelinating polyneuropathy and other immune-mediated neuropathies. Curr Opin Crit Care 2011;17:101–105. Dalakas MC: Clinical trials in CIDP and chronic autoimmune demyelinating polyneuropathies. J Peripher Nerv Syst 2012; 17: 34–39. Wolf C, Menge T, Stenner MP, et al: Natalizumab treatment in a patient with chronic inflammatory demyelinating polyneuropathy. Arch Neurol 2010;67:881–883. Graham RC, Hughes RA: A modified peripheral neuropathy scale: the overall neuropathy limitations scale. J Neurol Neurosurg Psychiatry 2006;77:973–976. Vallat JM, Tabaraud F, Magy L, et al: Diagnostic value of nerve biopsy for atypical chronic inflammatory demyelinating polyneuropathy: evaluation of eight cases. Muscle Nerve 2003;27:478–485. Van den Bergh PY, Hadden RD, Bouche P, et al: European federation of neurological societies/peripheral nerve society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European federation of neurological societies and the peripheral nerve society – first revision. Eur J Neurol 2010;17:356–363. Hughes RA, Swan AV, van Doorn PA: Cytotoxic drugs and interferons for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev 2004; 1:CD003280. Shimizu F, Omoto M, Sano Y, et al: Sera from patients with multifocal motor neuropathy
20
21 22
23
24
25
26
27
28
29
disrupt the blood-nerve barrier. J Neurol Neurosurg Psychiatry 2014;85:526–537. Kanda T: Biology of the blood-nerve barrier and its alteration in immune mediated neuropathies. J Neurol Neurosurg Psychiatry 2013;84:208–212. Hynes RO: Integrins: bidirectional, allosteric signaling machines. Cell 2002;110:673–687. O’Connor P: Natalizumab and the role of alpha 4-integrin antagonism in the treatment of multiple sclerosis. Expert Opin Biol Ther 2007;7:123–136. Yednock TA, Cannon C, Fritz LC, SanchezMadrid F, Steinman L, Karin N: Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 1992;356:63–66. Leussink VI, Zettl UK, Jander S, et al: Blockade of signaling via the very late antigen (VLA-4) and its counterligand vascular cell adhesion molecule-1 (VCAM-1) causes increased T cell apoptosis in experimental autoimmune neuritis. Acta Neuropathol 2002; 103:131–136. Enders U, Lobb R, Pepinsky RB, Hartung HP, Toyka KV, Gold R: The role of the very late antigen-4 and its counterligand vascular cell adhesion molecule-1 in the pathogenesis of experimental autoimmune neuritis of the Lewis rat. Brain 1998;121:1257–1266. Fox RJ, Cree BA, De Sèze J, et al: MS disease activity in RESTORE: a randomized 24-week natalizumab treatment interruption study. Neurology 2014;82:1491–1498. Kuwabara S, Misawa S, Mori M, Tamura N, Kubota M, Hattori T: Long term prognosis of chronic inflammatory demyelinating polyneuropathy: a five year follow up of 38 cases. J Neurol Neurosurg Psychiatry 2006; 77: 66– 70. Delbue S, Elia F, Carloni C, et al: JC virus urinary excretion and seroprevalence in natalizumab-treated multiple sclerosis patients. J Neurovirol 2014, Epub ahead of print. Van Assche G, Van Ranst M, Sciot R, et al: Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med 2005;353:362–368.
Vallat/Mathis/Ghorab/Milor/Richard/ Magy
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1 Vallat JM, Sommer C, Magy L: Chronic inflammatory demyelinating polyradiculoneuropathy: diagnostic and therapeutic challenges for a treatable condition. Lancet Neurol 2010;9:402–412. 2 Joint Task Force of the EFNS and the PNS: European federation of neurological societies/peripheral nerve society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European federation of neurological societies and the peripheral nerve society – first revision. J Peripher Nerv Syst 2010;15:1–9. 3 Querol L, Rojas-Garcia R, Casasnovas C, et al: Long-term outcome in chronic inflammatory demyelinating polyneuropathy patients treated with intravenous immunoglobulin: a retrospective study. Muscle Nerve 2013;48:870–876. 4 Dalakas MC, Engel WK: Immunoglobulin and complement deposits in nerves of patients with chronic relapsing polyneuropathy. Arch Neurol 1980;37:637–640. 5 Querol L, Nogales-Gadea G, Rojas-Garcia R, et al: Antibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy. Ann Neurol 2013;73:370–380. 6 Odaka M, Tatsumoto M, Susuki K, Hirata K, Yuki N: Intractable chronic inflammatory demyelinating polyneuropathy treated successfully with ciclosporin. J Neurol Neurosurg Psychiatry 2005;76:1115–1120. 7 Brannagan TH 3rd, Pradhan A, Heiman-Patterson T, et al: High-dose cyclophosphamide without stem-cell rescue for refractory cidp. Neurology 2002;58:1856–1858. 8 Cocito D, Grimaldi S, Paolasso I, et al: Immunosuppressive treatment in refractory chronic inflammatory demyelinating polyradiculoneuropathy. A nationwide retrospective analysis. Eur J Neurol 2011;18:1417–1421. 9 RMC Trial Group: Randomised controlled trial of methotrexate for chronic inflammatory demyelinating polyradiculoneuropathy (RMC trial): a pilot, multicentre study. Lancet Neurol 2009;8:158–164. 10 Dyck PJ, O’Brien P, Swanson C, Low P, Daube J: Combined azathioprine and predni-
Eur Neurol 2015;73:294–302 DOI: 10.1159/000381767
Natalizumab as a Disease-Modifying Therapy in Chronic Inflammatory Demyelinating Polyneuropathy – A Report of Three Cases Jean-Michel Vallat a Stéphane Mathis b Karima Ghorab a Michel-André Milor a Laurence Richard a Laurent Magy a
a
Department of Neurology, National Referral Center for ‘Rare Peripheral Neuropathies’, University Hospital Limoges, Limoges, and b Department of Neurology, University Hospital Poitiers, Poitiers, France
Abstract Background: Several treatments are available to treat the immune-mediated chronic inflammatory demyelinating polyneuropathy (CIDP). Among these treatments, intravenous immunoglobulins, corticosteroids and plasma exchanges are validated and widely used. A few immunosuppressive drugs have been tried, but they had little efficiency. Methods: We describe three CIDP patients treated by Natalizumab (acting against cellular adhesion and T-cell migration) after a failure of the validated treatments. Results: We observed a long-term improvement in one patient, a dramatic improvement over a significant duration in another patient and stabilization in the last one. Conclusion: This open label study provides evidence for the value of Natalizumab as second-line treatment for individual patients with a high dependency on waning efficacy of first-line therapies. CIDP is characterized by heterogeneity of clinical phenotypes, electrophysiological and pathological features, and various variable courses types of evolution. The different responses to drugs of our patients are consistent with some reported cases and may reflect the spectrum of lesional mechanisms and the molecular dysfunctions in CIDP. © 2015 S. Karger AG, Basel
© 2015 S. Karger AG, Basel 0014–3022/15/0736–0294$39.50/0 E-Mail [email protected] www.karger.com/ene
Introduction
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated neuropathy involving cellular and humoral immunity. It is clinically heterogeneous and generally symmetric sensorimotor neuropathy evolving as a monophasic, relapsing or progressive, disorder [1]. The current approach to treat this neuropathy is a suppression of autoimmune responses; intravenous immunoglobulins (IVIg), corticosteroids and plasma exchange have proven their efficacy and are used in the short and long terms [2]. The response to IVIg and plasma exchange supports a role for humoral factors and autoantibodies in CIDP [3], also provided by the presence of immunoglobulin G and complement in sural nerve biopsies [4]. Some axoglial antigens have been proposed as candidate antigens in a few CIDP patients [5]. In addition to these mechanisms, biological and histopathologic findings suggest that T cells play a key role in the pathogenesis of this disorder. The efficacy of immunosuppressants in CIDP has been suggested by some studies [6–8], but randomized controlled trials have failed to show any effect of immunosuppressants to date [9–11]. Other drugs have been used to treat patients with CIDP in a few series [12]. Some of these drugs act by selectively suppressing T cells (Alemtuzumab), B cells (Rituximab) or complement (Eculizumab), with various clinical efficacies [13]. Prof. Jean-Michel Vallat Department of Neurology, National Referral Center for ‘Rare Peripheral Neuropathies’ University Hospital Limoges, 2 Avenue Martin-Luther-King FR–87042 Limoges Cedex (France) E-Mail jean-michel.vallat @ unilim.fr
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Key Words Natalizumab · CIDP · Immune-mediated neuropathy · VLA4 · VCAM1 · Blood-nerve barrier
ONLS 12 11 10 9 8 7 6 5 4 3 2 1 0
Patient 1 0
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24
36
48
60
72
84
96
108
120
132
144
156
Duration (months) ONLS 12 11 10 9 8 7 6 5 4 3 2 1 0
Patient 2 0
12
24
36
48
60
72
84
96
108
120
132
144
156
Duration (months)
ONLS 12 11 10 9 8 7 6 5 4 3 2 1 0
Patient 3 0
12
24
36
48
60
72
84
96
108
120
132
144
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Duration (months) Natalizumab (monthly) Natalizumab (quarterly)
Oral corticosteroids
Infusion on intravenous immunoglobulins (0.4 g/kg/day during five days)
Subcutaneous immunoglobulins (weekly)
ENMG
Fig. 1. Course of CIDP (evaluation with total ONLS) for our three patients (with treatments used for each one). For patient 1, we observe a long-term improvement; for patient 2, the worsening tends to reverse (with relapse after each stopping of Natalizumab); for patient 3, slowly worsening and then stabilization was observed.
Natalizumab in CIDP
Observations
Informed consent was obtained from each patient after having explained the rationale of using Natalizumab in CIDP (but that it had not been validated as an efficient treatment in this indication) and its potential adverse effects. The clinical course of the disease (evaluated with the Total Overall Neuropathy Limitations Scale, or total ONLS) [15] and the use of Natalizumab (and other therapeutics) are shown in figure 1: the total duration of folEur Neurol 2015;73:294–302 DOI: 10.1159/000381767
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Among these alternative drugs, Natalizumab (used in the treatment of multiple sclerosis), acting against cellular adhesion and T-cell migration (by acting directly on the α4β1-integrin (also known as ‘very late antigen-4’ or VLA4) on leukocytes), might be a promising treatment for some immune-mediated neuropathies, even though it was found to be ineffective in one case of CIDP [14]. According to this rationale, we used Natalizumab in three patients with CIDP who presented very severe and frequent recurrent relapses over a number of years.
Patient 1 This 68-year-old woman (with a medical history of arterial hypertension and depression) was admitted to hospital for distal numbness in her upper limbs for a few months, before complaining of the same symptoms in her lower limbs, accompanied with gait ataxia and absent deep tendon reflexes (without weakness): the total ONLS score was 5/12 after 10 months. Electrophysiological findings were consistent with a demyelinating sensorimotor polyneuropathy (motor nerve conduction in upper limbs was 25–38 m/s, with increase of distal latencies) without severe active distal denervation in the lower limbs (presence of slight fibrillation in the tibialis anterior muscles) (table 1). The clinical and electrodiagnostic findings were consistent with the diagnosis of CIDP according to the EFNS/PNS criteria [2]. Laboratory tests only showed a serum IgG-kappa monoclonal gammopathy; no plasma cell expansion was found on bone marrow aspiration. The other ancillary tests were normal. AntiMAG and other anti-ganglioside (GM1, asialo-GM1, GM2, GD1a, GD1b, and GQ1b) antibodies were negative in the serum. Cerebrospinal fluid protein (CSF) content was elevated (88 mg/dl), without cells. On a sural nerve biopsy (performed at the age of 68 because of the rapid worsening), microscopical examination was in favor of CIDP: some T cells in the perineurium and a discrete loss of myelinated fibers (fig. 2) with features of a demyelinating process (with abnormally thinned myelin sheaths) were observed; the density of myelinated nerve fibers was 6,503/mm2 (7,618/mm2 for a normal control of the same age); by electron microscopy, we observed a variable degree of Schwann cell proliferations (‘onion bulb’ formations) around de- and re-myelinating fibers, but no abnormal deposits in the endoneurium. Direct immunofluorescence (frozen sections) did not show any abnormal deposits (fig. 2). Because of the severity of the sensory ataxia (causing substantial disability), regular and effective courses of IVIg were decided, albeit requiring periodic infusions. After 2 years, we observed an improvement with a total ONLS score at 2/12 (but with recurrent relapses each month) before observing a dramatic progressive worsening during the next year (total ONLS score was 8/12). At that time, oral prednisolone (at a daily dose of 60 mg) was given for 3 months, without any substantial improvement. So, 4 years after the beginning of the symptoms, 296
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perfusions of Natalizumab (13 monthly infusions, then six quarterly infusions) were added to IVIg. After 12 months of this combination, the patient presented a dramatic improvement of her sensory ataxia (without any relapse). She is now still fully ambulatory and has an almost complete disappearance of her numbness in the four limbs. Twenty-seven months after the beginning of Natalizumab, the total ONLS score was still 2/12 (1/12 one year later, 0/12 after six other months then stable). After 19 perfusions (fig. 1), Natalizumab was stopped because of the positivity of the JC virus serology (normal brain MRI). No IVIg treatment was needed after more than 60 months; 12 months after Natalizumab had been stopped, the electrophysiological study showed a mild decrease of motor distal latencies (except for the right tibial nerve) and a mild increase in CMAP amplitudes in all four limbs, but with a mild decrease of the motor NCV as well (table 1). Patient 2 A 70-year-old woman, with a medical history of cataract and basocellular carcinoma, complained of distal paresthesias in her lower limbs, and a few months later in her upper limbs (with bilateral attitude tremor in the upper limbs). After 8 months, she presented mild gait disturbance, without any motor deficit and general areflexia (total ONLS score: 4/12). Ten months later, nerve conduction studies were performed and showed a severe mainly distal sensorimotor demyelinating polyneuropathy with increased motor distal latencies and decreased motor nerve conduction velocities (NCVs) in the four limbs, also with some conduction blocks; no sensory nerve action potentials (SNAP) were recorded in all four limbs (table 1). CSF protein concentration was 33 mg/dl, without cells. Other ancillary tests ruled out other causes of peripheral neuropathy. As for the two other patients, there were no anti-MAG or other anti-ganglioside (GM1, asialo-GM1, GM2, GD1a, GD1b, and GQ1b) antibodies in the serum. The clinical and laboratory findings were judged consistent with the diagnosis of CIDP according to the EFNS/PNS criteria [2]. A treatment by IVIg was initiated because the patient was considered to have a significant disability caused by sensory ataxia and prominent tremor of both hands. Because of side effects after the second IVIg infusion (urticaria), the patient was treated by oral corticosteroids (1 mg/kg/day). No improvement was observed although there was a stabilization; it was decided to decrease slowly and then to stop steroids after 14 months. After this period, a treatment by subcutaneous immunoglobulins Vallat/Mathis/Ghorab/Milor/Richard/ Magy
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low-up of these patients (since the onset of symptoms) was 108 months for patient 1, 129 months for patient 2 and 160 months for patient 3.
Natalizumab in CIDP
Eur Neurol 2015;73:294–302 DOI: 10.1159/000381767
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297
lower limbs
upper limbs
lower limbs
upper limbs
Sensory study
Motor study
upper limbs
lower limbs
upper limbs
Before Natalizumab
Sensory study
Motor study
First ENMG
right left right left
radial nerve
right left
tibial nerve
median nerve
right left
right left
ulnar nerve
peroneal nerve
right left
right left
superficial peroneal nerve
median nerve
right left
right left
radial nerve
sural nerve
right left
median nerve
right left
tibial nerve
– ND
ND ND
18 ms –
25.1 ms 14.2 ms
3.88 ms ND
6.62 ms ND
– ND
2.1 ms 1.6 ms
– 1.5 ms
– ND
3.7 ms 5.5 ms
4.3 ms 4.2 ms
left right left
2.7 ms
right
ulnar nerve
peroneal nerve
4.2 ms
right left
median nerve
16.2 ms 3.8 ms
0 μV ND
ND ND
0.11 mV –
0.07 mV 0.91 mV
6 mV ND
4.4 mV ND
0 μV ND
11 μV 17 μV
0 μV 2.1 μV
0 μV ND
3.1 mV 4.0 mV
5.0 mV 5.8 mV
6.2 mV*
2.3 mV*
0.7 mV 3.1 mV*
– ND
ND ND
15.5 m/s –
27.4 m/s 18.8 m/s
16.6 m/s ND
20.9 m/s ND
– ND
44.3 m/s 40.1 m/s
– 49.3 m/s
– ND
37.5 m/s 40.8 m/s
39.3 m/s 41.5 m/s
37.9 m/s
35.3 m/s
25 m/s 31.6 m/s
NA NA
NA NA
– –
– –
– ND
– ND
NA NA
NA NA
NA NA
NA NA
71.3 ms ND
– –
–
55.1 ms
– –
ND ND
ND –
17.2 ms 12.7 ms
7.2 ms 6.8 ms
ND 6.1 ms
ND 7.3 ms
– –
– –
– –
– –
– –
13.2 ms 20.3 ms
12.7 ms
8.6 ms
13.1 ms 23.7 ms
distal latency
F wave
distal latency
distal conduction amplitude velocity
Patient 2
Patient 1
ND ND
ND 0 μV
0.5 mV 0.6 mV
1 mV 1.3 mV
ND 4 mV
ND 3.6 mV
0 μV –
0 μV 0 μV
0 μV 0 μV
0 μV 0 μV
0 mV 0 mV
0.3 mV* 0.2 mV
1.3 mV
1.7 mV
1.5 mV 1.1 mV
distal amplitude
ND ND
ND –
10.1 m/s ND
17 m/s 21.1 m/s
ND 16.6 m/s
ND 18.9 m/s
– –
– –
– –
– –
– –
19.3 m/s 20 m/s
27.5 m/s
30.6 m/s
20.3 m/s 22 m/s
conduction velocity
Table 1. Electrophysiological study of motor and sensory nerves, before and after treatment with Natalizumab
NA NA
NA NA
– –
– –
ND 55.8 ms
ND 72.5 ms
NA NA
NA NA
NA NA
NA NA
– –
– –
–
–
– 62.5 ms
F wave
ND ND
– –
ND ND
– –
ND ND
– –
– –
ND ND
ND ND
– –
ND ND
– –
ND
ND
21.0 ms 17.7 ms
distal latency
Patient 3
ND ND
0 μV 0 μV
ND ND
0 mV 0 mV
ND ND
0 mV 0 mV
0 μV 0 μV
ND ND
ND ND
0 μV 0 μV
ND ND
0 mV 0 mV
ND
ND
1.4 mV 0.1 mV*
distal amplitude
ND ND
– –
ND ND
– –
ND ND
– –
– –
ND ND
ND ND
– –
ND ND
– –
ND
ND
41 m/s 42 m/s
conduction velocity
NA NA
NA NA
NA NA
NA NA
NA NA
NA NA
ND ND
– –
ND
ND
– –
F wave
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Vallat/Mathis/Ghorab/Milor/Richard/ Magy
lower limbs
upper limbs
right left
right left
lower sural limbs nerve
superficial peroneal nerve
right left
radial nerve
right left
right left
tibial nerve
upper median limbs nerve
right left
right left
ulnar nerve
peroneal nerve
right left
right left
right left
median nerve
superficial peroneal nerve
sural nerve
ND ND
ND ND
2.08 ms ND
ND ND
10.9 ms ND
8.55 ms ND
3.11 ms ND
4.35 ms ND
ND ND
– –
ND ND
ND ND
11.7 μV ND
ND ND
0.85 mV ND
0.37 mV 2.2 mV*
7.4 mV* ND
4.6 mV ND
ND ND
0 μV 0 μV
ND ND
ND ND
– ND
ND ND
21.6 m/s ND
25.3 m/s 24.9 m/s
34.2 m/s ND
29 m/s ND
ND ND
– –
NA NA
NA NA
NA NA
NA NA
– ND
– –
44.7 ms ND
44.3 ms ND
NA NA
NA NA
ND ND
2.7 ms ND
ND –
ND ND
5.9 ms ND
3.8 ms ND
ND 5.2 ms
ND 8.2 ms
ND ND
– ND
distal latency
F wave
distal latency
distal conduction amplitude velocity
Patient 2
Patient 1
ND ND
2.5 μV ND
ND –
ND ND
1.1 mV ND
2.5 mV ND
ND 6.2 mV
ND 4.4 mV
ND ND
0 μV ND
distal amplitude
ND ND
28.1 m/s ND
ND –
ND ND
19.4 m/s ND
25.3 m/s ND
ND 23 m/s
ND 21.4 m/s
ND ND
– ND
conduction velocity
NA NA
NA NA
NA NA
NA NA
– ND
83.8 ms ND
ND 66.3 ms
ND 65.3 ms
NA NA
NA NA
F wave
– –
ND ND
ND ND
– –
ND ND
– –
ND ND
– –
– –
ND ND
distal latency
Patient 3
* Conduction block. NA = Not applicable; ND = no data; – = not obtainable. The time of each electrophysiological study is presented in figure 1.
Sensory study
After Natalizumab
Motor study
lower limbs
Table 1. (continued)
0 μV 0 μV
ND ND
ND ND
0 μV 0 μV
ND ND
0 mV 0 mV
ND ND
0 mV 0 mV
0 μV 0 μV
ND ND
distal amplitude
– –
ND ND
ND ND
– –
ND ND
– –
ND ND
– –
– –
ND ND
conduction velocity
NA NA
NA NA
NA NA
NA NA
NA NA
NA NA
F wave
Patient 3 A 34-year-old woman developed subacute distal paresthesias in her four limbs within 12 weeks. One year later, she presented a mild distal weakness of the lower limbs (Medical Research Council: grade 4 on the tibialis anterior muscles) with also a mild gait disturbance, distal hypoesthesia of the lower limbs and generalized areflexia (total ONLS score: 2/12). Nerve conduction studies showed a severe sensorimotor demyelinating polyneuNatalizumab in CIDP
Fig. 2. Sural nerve biopsy (electron microscopy section) of patient
1 showing too thin myelin sheath.
ropathy, with axonal loss in the lower limbs (no CMAP and SNAP) and some conduction blocks in the upper limbs; most of the nerves (particularly in the lower limbs) were not excitable (table 1). The ancillary tests ruled out another cause of peripheral neuropathy. There were no anti-MAG or anti-ganglioside antibodies (GM1, asialoGM1, GM2, GD1a, GD1b, and GQ1b) in the serum. An elevated protein level was observed in the CSF (110 mg/ dl), without cells. On a sural nerve biopsy (performed at the age of 36), we observed a significance loss of myelinated fibers with features of a demyelinating process, with thin myelin sheaths and by electron microscopy a variable degree of Schwann cell proliferations (‘onion bulb’ formations). Numerous axons had lost their myelin sheaths; the density of myelinated fibers was 2,881/mm2 (9,604/mm2 for a normal control of the same age). Overall, the clinical and laboratory findings were consistent with the diagnosis of CIDP according to the EFNS/PNS criteria [2]. We have previously presented some details of this patient (case 8 of Vallat et al. [16]). For the next 9 years, we first observed the stabilization with IVIg (one course every one, 2 or 3 months) before she developed a slowly progressive worsening (regular IVIg treatment did not induce any significant improvement at that time). After 10 years, multiple hypertrophic peripheral nerves were clinically palpable; at that time, a lumbar MRI was performed and showed an important hypertrophy of the nerve roots (fig. 3). Three years later, the total ONLS score was 6/12, and Natalizumab was begun because the patient was considered no longer responsive to IVIg: after 11 courses of monthly treatment (while Eur Neurol 2015;73:294–302 DOI: 10.1159/000381767
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(SCIg) was prescribed for 2 years: there was no improvement during the first year (total ONLS score was 4/12). Over the following year, the total ONLS score increased to 7/12 because of distal weakness of the lower limbs; furthermore, she again presented a severe attitude tremor of her upper limbs (without cerebellar symptoms or parkinsonism), with fluctuations depending of the course of the CIDP. Another treatment by IVIg (with a different trademark) was tried, without any side effect at this time. The patient’s state improved markedly, but she needed periodic infusions of IVIg (fig. 1). The electrophysiological study showed a decrease of motor distal latencies (except for the right tibial nerve) and a mild increase in CMAP in all four limbs; a decrease in the motor NCV and still no SNAP in the four limbs were also observed (table 1). After 1 year, because of a lack of improvement, we decided to add a monthly treatment with Natalizumab while continuing IVIg (one course every 2 months). The total ONLS score decreased slightly (5/12) after 11 monthly infusions of Natalizumab, and the frequency of IVIg infusions could be decreased (one every 4 months). After having stopped Natalizumab, the patient was stable for 5 months before an increase of tremor during three weeks; then a subacute worsening of gait disturbance happened (total ONLS: 7/12). Six months after having stopped Natalizumab, 8 monthly infusions of Natalizumab were prescribed again: a dramatic improvement with a disappearance of tremor and of gait ataxia (total ONLS: 3/12) was observed. At that time, because of a positiveness of the JC virus serology (but with normal brain MRI), Natalizumab was stopped again and CIDP symptoms and signs were stable for 6 months (total ONLS: 3/12); then, spontaneously, a subacute worsening appeared during the next month: total ONLS increased to 5/12 (with a stabilization during 5 months), then the total ONLS decreased 19 months after the end of the second course of Natalizumab (3/5) (fig. 1). The last ENMG (few weeks after the end of the second course of Natalizumab) showed an improvement in motor conduction velocities and amplitude in the four limbs (table 1).
Fig. 3. Lumbar MRI (coronal plane) showa
continuing IVIg), no significant clinical and/or electrophysiological improvement was observed, but a stabilization of the total ONLS score (6/12) one year after the end of the 12 monthly infusions of Natalizumab (fig. 1). Natalizumab was stopped because of a positivity of the JC virus serology (normal brain MRI). No adverse effect of Natalizumab (except regressive urticaria after the second course) was reported by the patient. After the end of Natalizumab treatment, the electrophysiological study showed no motor or sensory improvement in the four limbs (table 1). Finally, after about 14 years of evolution, we decided to stop IVIg and to propose plasma exchanges.
Discussion
Corticosteroids, plasma exchange (PE) and intravenous immunoglobulins (IVIg) are effective and are recommended to treat CIDP [2]; nevertheless, the ways in which these treatments act are not fully understood, in part because the mechanisms causing nerve damage in CIDP are themselves not completely known [1]. Because usual treatments of CIDP are not always effective and because some patients are highly dependent on high-dose IVIg or steroids, there is a need to find alternative treatments that may act as disease-modifying therapies. In this report, we have presented three patients with a severe sensory ataxic form of CIDP who had a clear benefit from adding Natalizumab to their usual treatment regimen. The term CIDP includes a remarkably heterogeneous group of phenotypes with different clinical courses, 300
Eur Neurol 2015;73:294–302 DOI: 10.1159/000381767
b
atypical variants, and sometimes the presence of a monoclonal gammopathy [17]. Underlying such variability, there is probably also a broad spectrum of immune events and molecular mechanisms that might explain the heterogeneity of response to treatments. Various immunosuppressants have been reported as being efficient in isolated cases [8, 18]; nevertheless, randomized control trials (RCT) of most of these drugs have failed to show any evidence of efficacy [9, 11]. Again, these discrepancies may stress the heterogeneity and complexity of mechanisms in CIDP. Recently, the presence of antibodies against conformational epitopes of the CNTN1/CASPR1 complex was confirmed in a subset of CIDP patients with similar clinical features such as higher age at onset, predominant motor symptoms, rapidly progressive course and partial or inexistent response to IVIg [5]. Finally, the benefits of recommended treatments (IVIg, steroids and PE) may be absent, inadequate or short-lived (lasting a few weeks) in some patients [11], so that alternative treatments have to be tried in reference centers. Some reports have shown that the pathological breakdown of the blood nerve barrier (BNB) (so that the nerve parenchyma is infiltrated by T cells and a variety of molecules such as immunoglobulins, cytokines and chemokines) is an important mechanism in the disease process of several types of dysimmune neuropathies [19]. Moreover, morphological abnormalities of endothelial cells and pathological changes of endoneurial microvessels (due to the alteration of tight junction proteins between endothelial cells) can be observed in some dysimmune neuropathies [20]. Vallat/Mathis/Ghorab/Milor/Richard/ Magy
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ing hypertrophy of the lumbar roots (arrows) on T1-weighted (a) and T2-weighted (b) sequences.
Natalizumab is a recombinant humanized α4-integrin monoclonal antibody originally derived from a murine antibody against α4-integrin, which belongs to the large family of adhesion receptors of the integrin family; it mediates both cell-extracellular matrix and cell-cell interactions [21]. The major endothelial ligand for α4-integrin is vascular cell adhesion molecule-1 (VCAM-1) that is upregulated on endothelial cells during inflammation. In consequence, Natalizumab appears to both prevent the recruitment of immune cells into inflamed tissue (by blocking the binding of α4-integrin to VCAM-1) and suppress the ongoing inflammatory activity (by interrupting the interaction between α4-integrin-expressing leukocytes and extracellular matrix proteins, such as fibronectin and osteopontin) [22]. In 1991, Yednock et al. first demonstrated that targeting α4-integrin could prevent the development of demyelinating lesions in a mouse model of multiple sclerosis (MS) [23]. So, Natalizumab was initially tried in chronic inflammatory diseases of the central nervous system, and it is now approved for the treatment of relapsing-remitting MS since 2004. Even if it is not fully understood, it is known that VLA4 and VCAM-1 participate in the pathogenesis of inflammatory diseases of the peripheral nervous system [24]. The experimental immunological blockade of VCAM-1 can reduce damage on peripheral nerve myelin (in animals with experimental autoimmune neuritis), but without offering a total protection for the nerve [25]. Recently, T cells expressing α4-integrin were demonstrated in the peripheral nerve of a CIDP patient [14]. However, despite a good targeting of T cells by Natalizumab, no positive clinical response was observed for this patient with a highly active form of CIDP. One of our three cases (patient 1) dramatically improved under Natalizumab treatment (13 monthly, then 6 quarterly courses), with long-term stabilization and definitive interruption of IVIg infusions; in that case, we envisage the progressive decrease of the dose of Natalizumab. Our patient 2 also improved after Natalizumab; a subacute relapse appeared 6 months after this treatment was interrupted; Natalizumab was tried again but finally stopped because of JC virus positivity, leading to a new relapse of the disease. In that case, and as for MS [26], we wondered if this severe relapse might have been due to the interruption of Natalizumab. For patient 3, the course of the disease was slowly progressive: Natalizumab apparently stopped the worsening, and the total ONLS score (6/12) seems to have been stabilized; considering this last patient, it has to be stressed that Natalizumab has been prescribed after 13 years (with severe axonal loss), so that significant clini-
cally palpable nerve lesions and on a lumbar MRI presence of a significant (an important) and diffuse hypertrophy of the root nerves were observed, as for the case of Wolf et al. [14]. It is known that axonal loss, correlated with a higher disability and a worst response to treatments, is the major long-term prognostic factor of CIDP [27]. These data suggest that the efficiency of Natalizumab may be correlated with the extent of the axonal loss. Moreover, it is also possible that nerve root hypertrophy, reflecting a chronic neuropathic process, may be a predictive factor of inefficiency of Natalizumab in CIDP. Finally, these variable responses to Natalizumab observed in our three patients might well reflect the heterogeneity of lesion mechanisms in CIDP. Although Natalizumab has been shown to be effective in MS and Crohn’s disease, there are concerns that some patients may develop progressive multifocal leukoencephalopathy (PML) under this treatment; risk factors for this rare side effect are duration of treatment (more than 24 infusions), previous treatment with immunosuppressants and a positive serodiagnosis test for JC virus [28]. Indeed, PML is caused by a reactivation of JC virus in the brain and this does not require blood-brain-barrier breakdown, as it has been described in a patient with Crohn’s disease [29]. It would therefore be reasonable to test for anti-JC virus antibodies before treating patients with Natalizumab, and exclude patients with a positive serodiagnostic test, unless no other alternative treatment is available. In conclusion, CIDP is an immune-mediated neuropathy that can usually be treated with IVIg, corticosteroids and plasma exchanges. However, probably because of the heterogeneity of the disease, an inadequate response to these first-line treatments is sometimes observed. In such patients, because of the BNB alteration in immune-mediated neuropathies, Natalizumab could be proposed as a second line of treatment. As such, severe CIDP cases are not very common and also because some of these cases might not respond to Natalizumab, it does not seem realistic to propose randomized controlled trials (RCT). In a first step, the use of Natalizumab could be considered on a case by case basis for patients who have not responded to treatments validated by RCT. More detailed and specific indications of Natalizumab might be determined after we find out more about the molecular dysfunction(s) in each case.
Natalizumab in CIDP
Eur Neurol 2015;73:294–302 DOI: 10.1159/000381767
Disclosure Statement
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The authors declare that they have no conflict of interest.
References
302
11
12
13
14
15
16
17
18
19
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sone in chronic inflammatory-demyelinating polyneuropathy. Neurology 1985; 35: 1173– 1176. Mahdi-Rogers M, Swan AV, van Doorn PA, Hughes RA: Immunomodulatory treatment other than corticosteroids, immunoglobulin and plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev 2010; 11: CD003280. Magy L, Mathis S, Vallat JM: Diagnostic and therapeutic challenges in chronic inflammatory demyelinating polyneuropathy and other immune-mediated neuropathies. Curr Opin Crit Care 2011;17:101–105. Dalakas MC: Clinical trials in CIDP and chronic autoimmune demyelinating polyneuropathies. J Peripher Nerv Syst 2012; 17: 34–39. Wolf C, Menge T, Stenner MP, et al: Natalizumab treatment in a patient with chronic inflammatory demyelinating polyneuropathy. Arch Neurol 2010;67:881–883. Graham RC, Hughes RA: A modified peripheral neuropathy scale: the overall neuropathy limitations scale. J Neurol Neurosurg Psychiatry 2006;77:973–976. Vallat JM, Tabaraud F, Magy L, et al: Diagnostic value of nerve biopsy for atypical chronic inflammatory demyelinating polyneuropathy: evaluation of eight cases. Muscle Nerve 2003;27:478–485. Van den Bergh PY, Hadden RD, Bouche P, et al: European federation of neurological societies/peripheral nerve society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European federation of neurological societies and the peripheral nerve society – first revision. Eur J Neurol 2010;17:356–363. Hughes RA, Swan AV, van Doorn PA: Cytotoxic drugs and interferons for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev 2004; 1:CD003280. Shimizu F, Omoto M, Sano Y, et al: Sera from patients with multifocal motor neuropathy
20
21 22
23
24
25
26
27
28
29
disrupt the blood-nerve barrier. J Neurol Neurosurg Psychiatry 2014;85:526–537. Kanda T: Biology of the blood-nerve barrier and its alteration in immune mediated neuropathies. J Neurol Neurosurg Psychiatry 2013;84:208–212. Hynes RO: Integrins: bidirectional, allosteric signaling machines. Cell 2002;110:673–687. O’Connor P: Natalizumab and the role of alpha 4-integrin antagonism in the treatment of multiple sclerosis. Expert Opin Biol Ther 2007;7:123–136. Yednock TA, Cannon C, Fritz LC, SanchezMadrid F, Steinman L, Karin N: Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 1992;356:63–66. Leussink VI, Zettl UK, Jander S, et al: Blockade of signaling via the very late antigen (VLA-4) and its counterligand vascular cell adhesion molecule-1 (VCAM-1) causes increased T cell apoptosis in experimental autoimmune neuritis. Acta Neuropathol 2002; 103:131–136. Enders U, Lobb R, Pepinsky RB, Hartung HP, Toyka KV, Gold R: The role of the very late antigen-4 and its counterligand vascular cell adhesion molecule-1 in the pathogenesis of experimental autoimmune neuritis of the Lewis rat. Brain 1998;121:1257–1266. Fox RJ, Cree BA, De Sèze J, et al: MS disease activity in RESTORE: a randomized 24-week natalizumab treatment interruption study. Neurology 2014;82:1491–1498. Kuwabara S, Misawa S, Mori M, Tamura N, Kubota M, Hattori T: Long term prognosis of chronic inflammatory demyelinating polyneuropathy: a five year follow up of 38 cases. J Neurol Neurosurg Psychiatry 2006; 77: 66– 70. Delbue S, Elia F, Carloni C, et al: JC virus urinary excretion and seroprevalence in natalizumab-treated multiple sclerosis patients. J Neurovirol 2014, Epub ahead of print. Van Assche G, Van Ranst M, Sciot R, et al: Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med 2005;353:362–368.
Vallat/Mathis/Ghorab/Milor/Richard/ Magy
Downloaded by: University of Tokyo 157.82.153.40 - 5/13/2015 6:47:38 PM
1 Vallat JM, Sommer C, Magy L: Chronic inflammatory demyelinating polyradiculoneuropathy: diagnostic and therapeutic challenges for a treatable condition. Lancet Neurol 2010;9:402–412. 2 Joint Task Force of the EFNS and the PNS: European federation of neurological societies/peripheral nerve society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European federation of neurological societies and the peripheral nerve society – first revision. J Peripher Nerv Syst 2010;15:1–9. 3 Querol L, Rojas-Garcia R, Casasnovas C, et al: Long-term outcome in chronic inflammatory demyelinating polyneuropathy patients treated with intravenous immunoglobulin: a retrospective study. Muscle Nerve 2013;48:870–876. 4 Dalakas MC, Engel WK: Immunoglobulin and complement deposits in nerves of patients with chronic relapsing polyneuropathy. Arch Neurol 1980;37:637–640. 5 Querol L, Nogales-Gadea G, Rojas-Garcia R, et al: Antibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy. Ann Neurol 2013;73:370–380. 6 Odaka M, Tatsumoto M, Susuki K, Hirata K, Yuki N: Intractable chronic inflammatory demyelinating polyneuropathy treated successfully with ciclosporin. J Neurol Neurosurg Psychiatry 2005;76:1115–1120. 7 Brannagan TH 3rd, Pradhan A, Heiman-Patterson T, et al: High-dose cyclophosphamide without stem-cell rescue for refractory cidp. Neurology 2002;58:1856–1858. 8 Cocito D, Grimaldi S, Paolasso I, et al: Immunosuppressive treatment in refractory chronic inflammatory demyelinating polyradiculoneuropathy. A nationwide retrospective analysis. Eur J Neurol 2011;18:1417–1421. 9 RMC Trial Group: Randomised controlled trial of methotrexate for chronic inflammatory demyelinating polyradiculoneuropathy (RMC trial): a pilot, multicentre study. Lancet Neurol 2009;8:158–164. 10 Dyck PJ, O’Brien P, Swanson C, Low P, Daube J: Combined azathioprine and predni-
