Atherosclerosis Supplements 14 (2013) 219e222
www.elsevier.com/locate/atherosclerosis
Immunoadsorption in patients with autoimmune ion channel disorders
of the peripheral nervous system
Carlo Antozzi*
Neuroimmunology and Muscle Pathology Unit, National Neurological Institute Foundation “Carlo Besta”, Via Celoria 11, 20133 Milan, Italy
Abstract
Autoimmune ion channel disorders of the peripheral nervous system include myasthenia gravis, the LamberteEaton myasthenic
syndrome, acquired neuromyotonia and autoimmune autonomic ganglionopathies. These disorders are characterized by the common feature
of being mediated by IgG autoantibodies against identified target antigens, i.e. the acetylcholine receptor, the voltage-gated calcium and
potassium channels, and the neuronal acetylcholine receptor. Moreover, experimental animal models have been identified for these diseases
that respond to immunotherapy and are improved by plasmapheresis. On this basis, autoimmune ion channel disorders represent the ideal
candidate for therapeutic apheresis. Immunoadsorption can be the treatment of choice when intensive apheretic protocols or long-term
treatments must be performed, in patients needing frequent apheresis to keep a stable clinical condition, in case of unresponsiveness to
corticosteroids and immunosuppressive treatments, or failure with TPE or intravenous immunoglobulins, and in patients with severe
contraindications to long-term corticosteroids.
Ó 2012 Elsevier Ireland Ltd. All rights reserved.
The ideal apheretic approach should remove only pathogenic autoantibodies leaving all the other plasma
components unaltered. Such a specific approach is not yet
available in clinical practice, but semiselective immunoadsorption (IA) represents an effective alternative, being
able to remove only circulating immunoglobulins (IgGs)
and hence the specific autoantibody involved in the pathogenesis of the disease under treatment. In this regard,
autoimmune ion channel disorders represent the ideal
candidate for this kind of apheretic approach.
Autoimmune ion channel disorders of the peripheral
nervous system share common pathogenetic features since
they are caused by specific autoantibodies against target
antigens. Target antigens identified so far include: 1) the
acetylcholine receptor (AChR) and the muscle specific
tyrosine kinase (MuSK) in the case of Myasthenia Gravis
(MG) [1], 2) the voltage-gated calcium channel (VGCC) of
* Tel.: þ39 02 239432255/2361; fax: þ39 02 70633874.
E-mail address: [email protected].
1567-5688/$ - see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.atherosclerosissup.2012.10.027
the presynaptic membrane associated with the LamberteEaton myasthenic syndrome (LEMS) [2], 3) the
voltage-gated potassium channel (VGKC) associated with
Acquired Neuromyotonia (NM) [3], and 4) the ganglionic
AChR associated with the Autoimmune Autonomic
Neuropathies (AAN) [4]. All diseases mentioned above are
caused by IgG autoantibodies, respond to immunotherapy,
are improved by plasmapheresis, and experimental animal
models have been identified for all of them.
Therapeutic plasmaexchange (TPE) is the technique of
choice for acute clinical conditions or short protocols,
could be easily administered to the majority of patients and
is usually safe [5]. However, in selected patients IA could
be the treatment of choice for several reasons. From
a technical standpoint, IA either with protein A or with
polyclonal sheep anti-human IgG is performed with two
filters that are continuously regenerated during the procedure thus allowing treatment of unlimited amounts of
plasma without the need for any replacement fluid [6].
Therefore, intensive protocols or long-term treatments can
be performed by IA in patients showing unresponsiveness
220
C. Antozzi / Atherosclerosis Supplements 14 (2013) 219e222
to steroids and immunosuppressive drugs, in case of failure
with TPE or intravenous immunoglobulins, or in case of
severe contraindications to long-term corticosteroids, or
when TPE must be performed very frequently to keep
a stable clinical condition. IA is more expensive, technically more complicated and time consuming compared with
TPE and therefore we favor its use in these selected clinical
conditions. Our protocol consists of three sessions performed two days apart, with treatment of two plasma
volumes during each session; subsequently, we repeat one
or two sessions every month depending on the patients’
clinical conditions; once they are stabilized we try to
increase the interval between sessions, and when the
interval is longer than two months we try to discontinue IA
[7].
Different semiselective systems are available for use in
clinical practice. We used both protein A as well as polyclonal sheep anti-human IgG columns with similar results
in terms of clinical efficacy and efficiency in IgG removal.
Protein A is a component of the staphylococcal cell wall
with the particular feature of binding human immunoglobulins with high affinity; the binding is thought to be
mediated by the Fc fragment of immunoglobulins; also, the
protein itself has negligible interaction with other plasma
components, is stable to wide variations in temperature and
pH, and can be easily regenerated. Sheep anti-human IgG
remove directly immunoglobulins by means of an immunological interaction. In both cases, two columns are used
during each procedure, performing alternatively IgG
adsorption of the patient’s plasma obtained by centrifugation or IgG elution. The alternate shift between adsorption
and elution overcomes the issue of column saturation and
thus makes these techniques suitable for treatment of
unlimited amounts of plasma, allowing intensive and/or
prolonged immunomodulating protocols [6].
1. Myasthenia gravis
MG is an autoimmune disorder of the neuromuscular
junction characterized by muscle weakness and fatigability
caused by specific antibodies against the AChR on the postsynaptic membrane [1]. TPE is rapidly effective in MG,
particularly in patients with bulbar muscles impairment [5].
Antibodies to MuSK have been more recently reported in
a proportion of patients without anti-AChR antibodies.
MuSK-associated MG, at least at onset, is characterized by
involvement of ocular and bulbar muscles and is frequently
complicated by respiratory insufficiency [8]. Both forms
respond very well and rapidly to TPE that is the apheretic
treatment of choice in patients with acute clinical deterioration. On the contrary, IA can be periodically and safely
performed in patients needing frequent apheresis to maintain a satisfactory improvement, in case of unresponsiveness to standard pharmacological treatment with
prednisone and immunosuppressive drugs, or contraindications to prolonged high dose corticosteroids. A few
experiences have been reported in the literature on the
efficacy of IA in MG ([7,9e11], and Table 1). We observed
a positive outcome in 19 out of 20 MG patients submitted
to IA with progressive clinical improvement and significant
reduction of corticosteroid dosage along the clinical follow
up. The absence of detectable anti-AChR or anti-MuSK
antibodies is not a contraindication to semiselective IA
that was indeed particularly effective in a patient with
“double negative” MG. The report of low affinity antibodies in patients with double negative MG may account
for the response to apheresis in these patients [12]. In our
experience with protein A, a mean of 71% reduction of
total IgG and 82% reduction of anti-AChR antibodies was
observed [7]. As expected, IgG and anti-AChR antibody
levels increased after each treatment likely due to IgG
backflow from the extravascular compartment; moreover,
we did not observe an increased synthesis of total IgG or
anti-AChR antibodies and the time course of autoantibody
recovery was consistent with immunoglobulin half-life.
A different kind of semiselective immunoadsorption is
based on filters containing tryptophane-linked polyvinyl
alcohol gel; the binding is mediated by a chemical interaction and is less selective than protein A or anti-human
IgG since other plasma components are retained, such as
fibrinogen and complement. Nevertheless, promising
results have been reported from a clinical point of view
[13]. The commercially available device is conceived as
a disposable single use filter.
Treatment protocols so far adopted with protein A, antihuman IgG or tryptophane columns are extremely
Table 1
Experience with different IA techniques in myasthenia gravis.
IA method
Pts
treated
# Sessions/
cycle
Duration
Reference
Try-PVA
7
9
8
2
16
5
34
1
9
3
6
6
2
4
5
//
3
3e5
1 week
2 weeks
3e6 weeks
2 days
8 days
10 days
Long-term
6 days
7 days
Sato, 1988 [14]
Hosokawa, 1990 [15]
Splendiani, 1991 [16]
Ichikawa, 1993 [17]
Grob, 1995 [13]
Yeh, 2000 [18]
Munakata, 2002 [19]
Ishizeki, 2005 [20]
Kohler, 2011 [21]
Protein A
1
1
3
//
6 days
Long-term
3
12
4
3
2
3
Long-term
3e5 days
3 days
13
6
10
//
3
3
Long-term
Long-term
6 days
Antozzi, 1994 [9]
Flachenecker,
1998 [22]
Berta, 1994 [7]
Benny, 1998 [10]
Schneidewind,
1999 [23]
Haas, 2002 [11]
Baggi, 2008 [24]
Liu 2009 [25]
5
15
6
2
5
//
Long-term
Long-term
Long-term
Ptak, 2004 [26]
Zeitler, 2006 [27]
Blaha, 2011 [28]
Anti-human
IgG
//: Prolonged treatment, total number of sessions variable.
C. Antozzi / Atherosclerosis Supplements 14 (2013) 219e222
heterogeneous in terms of number of sessions and duration
and therefore not easily comparable. A list of experiences
with different immunoadsorption techniques in MG is reported in Table 1.
221
anti-VGKC associated disorders has been the object of
a reassessment regarding clinical associations and specific
immunoreactivities, a recently identified and expanding
spectrum of disorders that might be an indication to IA in
the future [32].
2. The LamberteEaton myasthenic syndrome (LEMS)
4. Autoimmune autonomic ganglionopathy (AAG)
LEMS is caused by antibodies against the presynaptic
voltage-gated calcium channel (VGCC). Autoantibodies
cross-link their target (VGCC) that is depleted by means of
antigenic modulation [2]. As a consequence, acetylcholine
release is reduced with impairment of the neuromuscular
transmission. The disease is usually treated in the majority
of patients with the association of prednisone and azathioprine exerting a slow but positive effect. Because of the
chronic course of the disease, LEMS is a candidate to
immunomodulation with IgG adsorption. No series of
patients with LEMS submitted to IA have been reported in
the literature. We had the opportunity to treat six patients
with LEMS; in one patient the disease started after ovarian
cancer, and in another one after bone marrow transplantation. All patients were treated for at least one year.
We observed clinical improvement in five of them (two
patients that were wheelchair-bound regained walking)
[23]. Clinical improvement was correlated with neurophysiological findings (i.e. increase of the compound
muscle action potential). No effect was observed on cerebellar ataxia in one patient affected with the rare association of LEMS and cerebellar degeneration, likely due to
irreversible brain damage. However, the opposite finding
has been recently described [29].
3. Acquired NeuroMyotonia (NM)
NM is characterized by continuous fasciculations,
muscle cramps, fatigability and excessive sweating; the
presence of thymoma has been also reported. Some patients
may show signs of involvement of the central nervous
system with seizures, personality changes and sleep
disturbances, a variant called Morvan syndrome [3]. Both
conditions have been associated with antibodies against the
presynaptic voltage-gated potassium channel (VGKC).
Anti-VGKC antibodies interfere with the process of repolarization causing peripheral nerve hyperexcitability that
can be easily recorded neurophysiologically. We had the
opportunity to treat one patient with typical NM-Morvan
syndrome with rapid resolution of hyperhydrosis and
peripheral nerve hyperexcitability as observed clinically
and by neurophysiology with disappearance of the typical
afterdischarges. Interestingly, the patient’s purified IgG
stained neurons in different areas of the brain with colocalization with potassium channels Kv1.6 [30]. Our
patient was treated by means of protein A immunoadsorption; positive findings have also been reported in
a patient with Isaac’s syndrome treated with tryptophanelinked polyvinyl alcohol gel columns [31]. The chapter of
Synaptic transmission within autonomic ganglia is
mediated by acetylcholine acting on nicotinic AChR
(nAChR) that is similar to the muscle AChR at the neuromuscular junction. Several experimental data collected in
recent years suggested that in some patients dysfunction of
the autonomic nervous system can be due to autoimmunity
to the nAChR. Indeed, Tg mice homozygous for null
mutations in the alfa3 gene lack ganglionic AChR and show
severe autonomic failure. Experimental AAG could be
induced in rabbits immunized with a recombinant alfa3
subunit, and passive transfer of human IgG to mice causes
reversible dysautonomia [4]. AAG is a subacute disorder
associated with antibodies to nAChR. These autoantibodies
cause inhibition of synaptic transmission in autonomic
ganglia and their levels correlate with the severity of
autonomic failure. The majority of patients shows orthostatic hypotension associated with variable impairment of
the autonomic nervous system without evidence of somatic
neuropathy or involvement of the central nervous system.
Plasma norepinephrine levels are reduced and do not
increase during standing. Variable phenotypes have been
reported, from pure autonomic failure to limited autonomic
dysfunction and the postural tachycardia syndrome. Several
case reports suggest that AAG can be improved by
immunomodulation. Apart from pharmacological treatments, apheresis can be considered. We had the opportunity
to treat a male patient affected with AAG characterized
mainly by postural hypotension with positive anti-nAChR
antibodies. We first tried a short course of TPE with
immediate response and hence started periodic IA with
stable improvement, disappearance of orthostatic hypotension and normalization of norepinephrine levels. The
attempt to delay IA for more than two months were associated with reappearance of postural hypotension (personal
observation).
5. Conclusions
MG is undoubtedly the ideal candidate and the most
frequent indication to IA among autoimmune ion channel
disorders. The investigation of selective apheretic techniques for MG is under way thanks to the knowledge of the
AChR and to availability of recombinant fragments of the
AChR [33]. LEMS, NM and AAN are very rare disorders,
the reason why no series of patients or validated protocols
are available for their treatment. Nevertheless, the severity
of these disorders, together with their proven IgG mediated
pathogenesis, represent the rationale for the application of
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C. Antozzi / Atherosclerosis Supplements 14 (2013) 219e222
IA in selected patients. It is likely that their spectrum will
widen in the future, as indeed occurred for anti-potassium
channel disorders, now spanning from the peripheral
nervous system to immunotherapy responsive encephalopathies [32].
Conflicts of interest
None.
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