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Amphiphysin autoimmunity Paraneoplastic accompaniments.

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Amphiphysin Autoimmunity: Paraneoplastic
Accompaniments
Sean J. Pittock, MD,1,2 Claudia F. Lucchinetti, MD,1 Joseph E. Parisi, MD,1,2 Eduardo E. Benarroch, MD,1
Bahram Mokri, MD,1 Christina L. Stephan, MD,2 Kwang-Kuk Kim, MD, PhD,3 Manfred W. Kilimann, MD,4
and Vanda A. Lennon, MD, PhD1,2,5
Amphiphysin-IgG was identified in 71 patients among 120,000 evaluated serologically for paraneoplastic autoantibodies.
Clinical information was available for 63 patients. Cancer was detected in 50 (mostly limited), proven histologically in
46, and was imaged intrathoracically in 4 patients (lung, small–cell [27] and non–small cell [1]), breast [16] and melanoma [2]). Neurological accompaniments included (decreasing frequency): neuropathy, encephalopathy, myelopathy,
stiff-man phenomena, and cerebellar syndrome. In a case examined neuropathologically, parenchymal T-lymphocyte
infiltration (predominantly CD8ⴙ) was prominent in lower brainstem, spinal cord, and dorsal root ganglion. Coexisting
paraneoplastic autoantibodies, identified in 74% of patients, predicted a common neoplasm and indicated other neuronal
autoantigen targets that plausibly explained several neurological manifestations; for example, P/Q-type Ca2ⴙ-channel
antibody with Lambert–Eaton syndrome (n ⴝ 5), anti-neuronal nuclear antibody type 1 with sensory neuronopathy (n ⴝ
7), Kⴙ-channel antibody with limbic encephalitis (n ⴝ 1) or neuromyotonia (n ⴝ 1), and collapsin response-mediator
protein-5-IgG with optic neuritis (n ⴝ 3). Patients with isolated amphiphysin-IgG (n ⴝ 19) were more likely to be
women (with breast cancer, p < 0.05) and to have myelopathy or stiff-man phenomena (p < 0.01). Overall, a minority
of women (39%) and men (12%) had stiff-man phenomena. Only 10% of women (some with lung carcinoma) and 4%
of men fulfilled diagnostic criteria for stiff-man syndrome.
Ann Neurol 2005;58:96 –107
The synaptic vesicle protein amphiphysin was discovered in 1992 by Lichte and colleagues.1 It plays a critical role in retrieving vesicle membranes from the axon
terminal’s plasma membrane after depolarizationinduced exocytosis of neurotransmitter. In 1993, De
Camilli and colleagues2 first reported an autoantibody
specific for amphiphysin in the serum of three women
who presented with “paraneoplastic stiff-man syndrome” associated with breast carcinoma. In contrast
to patients with classic stiff-man (Moersch–Woltman)
syndrome,3 patients initially reported to have the paraneoplastic syndrome lacked detectable glutamic acid
decarboxylase– 65 (GAD65) autoantibody.4 In 1996,
Dropcho5 reported detection of amphiphysin autoantibody in three patients who had paraneoplastic encephalomyelitis associated with small–cell lung carcinoma;
some had sensory neuropathy. Subsequent case reports
suggest a broader spectrum of neurological manifestations with amphiphysin autoimmunity, and coexisting
paraneoplastic autoantibodies have been identified in
some patients.6 – 8
Autoantibodies currently recognized in serum and
spinal fluid as markers of paraneoplastic neurological
disorders include four reactive with neuronal nuclear
proteins (anti-neuronal nuclear antibody [ANNA] type
1 [anti-Hu], ANNA-2 [anti-Ri], ANNA-3, and
ANNA-Ma2) and five reactive with neuronal cytoplasmic proteins (Purkinje cell cytoplasmic antibody [PCA]
type 1, PCA-2, PCA-Tr, collapsin response-mediator
protein [CRMP]-5-IgG, and amphiphysin-IgG). Unlike plasma membrane antigens, in which some
epitopes are accessible to pathogenic IgG,9,10 intracellular antigens are inaccessible to circulating autoantibodies in the context of viable neurons. However, these
antigens are readily accessible to antibodies after death
or during cryosectioning. The passive transfer of IgG
directed at a tissue-restricted intracellular antigen does
not transfer organ-specific disease. Furthermore, active
From the Departments of 1Neurology and 2Laboratory Medicine
and Pathology, Mayo Clinic College of Medicine, Rochester, MN;
3
Department of Neurology, University of Visan College of Medicine, Seoul, Korea; 4Department of Cell and Molecular Biology,
Uppsala University Biomedical Center, Uppsala, Sweden; and 5Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN.
Published online Jun 27, 2005, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20529
Address correspondence to Dr Lennon, Neuroimmunology Laboratory, Guggenheim Building, Rm. 828, Mayo Clinic, 200 First Street
S.W., Rochester, MN 55905. E-mail: lennon.vanda@mayo.edu
Received Dec 29, 2004, and in revised form Apr 11 and Apr 27,
2005. Accepted for publication Apr 29, 2005.
96
© 2005 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
immunization of animals with intracellular onconeural
proteins thus far has not induced clinical signs or histopathological outcomes consistent with any human
neurological disorders. In contrast, a pathogenic role
has been ascribed to autoreactive cytotoxic T cells that
infiltrate both the tumor and nervous system of patients,11–13 and CD8⫹ T cells derived from patients
with paraneoplastic neurological autoimmunity have
been demonstrated to kill target cells expressing a defined neuronal peptide in the context of an appropriate
surface major histocompatibility complex (MHC) class
I molecule.14
In this study, we report the frequency of
amphiphysin-IgG detection among sera submitted to a
high-volume diagnostic laboratory for evaluation of
paraneoplastic autoantibodies, the frequency of coexisting neuronal and muscle autoantibodies and, for 63
patients, the range of neurological manifestations and
cancers identified. In addition, we describe the detailed
immunopathological findings for one patient.
Patients and Methods
Patients
In the last 15 years, Mayo Clinic’s Neuroimmunology Laboratory performed prospective indirect immunofluorescence
screening on sera from approximately 120,000 patients with
a subacute neurological presentation that was suspected to be
paraneoplastic. Amphiphysin autoantibody was detected in
the sera of 71 patients. We analyzed all of these sera for
coexisting autoantibodies. Insufficient information excluded
8 patients from the clinical review; 23 of the remaining 63
patients were evaluated clinically at the Mayo Clinic. Information for the other 40 patients was obtained by physician
telephone interview, form letters, and review of case records
provided by outside physicians. The study was approved by
the Institutional Review Board of Mayo Clinic Rochester
(IRB 1541-03).
Serological Evaluation
To detect IgG specific for neuronal nuclear antigens
(ANNA-1, -2, and -3) and neuronal cytoplasmic antigens
(amphiphysin-IgG, PCA-1, PCA-2, PCA-Tr, and CRMP-5IgG), we used a frozen composite substrate of mouse cerebellum, gut, and kidney, cut in 4␮m-thick sections and postfixed with 10% formalin.15,16 We defined amphiphysin-IgG
by immunohistochemical characteristics (Fig 1), and always
confirmed autoantibody specificities by Western blot analysis
using antigenic proteins in an aqueous extract of adult rat
cerebellum and also using recombinant proteins corresponding to human amphiphysin (residues 312-695) and CRMP-5
(full-length).
As described previously,17–19 we assayed antibodies reactive with cation channels (calcium channels [neuronal
voltage-gated P/Q-type and N-type], potassium channels
[␣-dendrotoxin–sensitive] and nicotinic acetylcholine receptors extracted from ganglionic neurons and muscle), skeletal
muscle striational antigens, thyroid (peroxidase and thyroglobulin), and recombinant human GAD65.
Neuropathological Evaluation
Two patients were studied. For one (Patient 7; see Tables 1
and 2), the autopsy information was limited to brain neuropathology. The other (Patient 31; see Tables 3 and 4) had a
complete autopsy performed 4 hours after death, including
examination of brain, spinal cord, and ganglia. Representative sections of formalin-fixed, paraffin-embedded tissues
were stained with hematoxylin and eosin and Luxol fast blue.
Selected sections (5␮m-thick paraffin) were stained immunohistochemically using commercial antibodies specific for glial
fibrillary acid protein (astrocyte marker; DakoCytomation,
Carpinteria, CA), CD3 (pan-T cell marker; Serotec, Raleigh,
NC), CD8 (cytotoxic T cells; DakoCytomation), CD20 (B
cells; DakoCytomation), and Kim1P (macrophages/microglial cells; gift from Dr W. Bruck, Gottingen, Germany).
Each reagent antibody was visualized by sequentially applying biotinylated IgG directed at the primary species’ IgG,
then avidin-peroxidase and diaminobenzidine as the chromogenic substrate.20 Alternatively, an alkaline-phosphatase–
based system was applied using fast red for visualization of
bound primary antibody.21
Results
Frequency of Amphiphysin Autoantibody Detection
The detection of amphiphysin antibody in 71 patients
over a 15-year period represents 0.06% of 120,000
neurological patients whose sera were submitted for
paraneoplastic autoantibody evaluation. By comparison, approximate detection frequencies for other neuronal nuclear and cytoplasmic autoantibodies were
0.4% for both ANNA-1 and CRMP-5-IgG, 0.2% for
PCA-1, 0.1% for PCA-2, 0.02% for ANNA-2, 0.01%
for ANNA-3, and 0.002% for PCA-Tr. The frequency
of ANNA-Ma2 is unknown.
Patient Demographics
Complete serological, neurological, and oncological
data for 63 seropositive patients are summarized in the
Tables. Most patients were white; 25 (40%) were male
patients (see Tables 1 and 2) and 38 (60%) were female (see Tables 3 and 4). The mean age (⫾ standard
error) was 64 (⫾10) years. Longitudinal information
was available for a mean duration of 18 months. Thirteen patients died (mean 25 ⫾ 18 months after onset
of neurological symptoms).
Oncological Associations
By the end of the follow-up period, a malignant neoplasm was detected in 50 of 63 patients (79%); a majority were limited in metastasis. In 46 patients (73%),
the cancer was confirmed histologically as a carcinoma
of the lung (28 total patients: 27 with small-cell and 1
with large-cell carcinoma) or breast (16 patients), or as
a melanoma (2 patients); the remaining 4 patients (all
smokers) had imaging evidence of lung cancer. The
neurological presentation preceded cancer detection in
45 (90%) of these 50 patients. The mean follow-up for
Pittock et al: Amphiphysin Autoimmunity
97
Fig 1. Immunofluorescence shows binding of IgG in a patient’s serum (at 1:120 dilution) to a composite substrate of mouse cerebellum, midbrain, gut mucosa and smooth muscle, and kidney (original magnification ⫻50): intense synaptic staining of the cerebellar
cortical molecular layer (ML), granular cell layer (GL, synaptic patches render a cobblestone pattern) and midbrain (MB). Purkinje
neurons are unstained. Stained enteric neural elements are seen throughout the smooth muscle layer (SM). The kidney (K) and mucosa (M) are unstained.
the 13 patients in whom a malignant neoplasm was
not detected was 23.2 ⫾ 21.4 months (median, 18
months; range, 0 – 60 months). A cancer was identified
in 21 (91%) of the 23 patients evaluated and managed
at the Mayo Clinic. The mean interval from neurological symptom onset to cancer detection overall was 9 ⫾
9 months (median, 5 months; range, 0 –39 months).
In 20 patients, cancer was not identified in the initial
investigation, but was detected in the course of continued surveillance. Positron emission tomography enabled tumor detection in several patients whose chest
computed tomography images were negative.
Autoimmune Serology
We found one or more additional neuronal, muscle,
or other organ-specific autoantibody in 74% of the
total study group of 71 patients. These additional autoantibody specificities included: Ca2⫹ channel (20
patients; P/Q-type 16, N-type 17), GAD65 (19 patients; median value, 0.17nM; range, 0.05– 8.03nM),
CRMP-5 (16 patients), thyroglobulin or thyroperoxi-
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Annals of Neurology
Vol 58
No 1
July 2005
dase (11 patients), ANNA-1 (10 patients), ganglionic
(␣III) acetylcholine receptor (7 patients), striational
(4 patients), K⫹ channel (3 patients), muscle acetylcholine receptor (3 patients), PCA-2 (2 patients), or
ANNA-2 (1 patient).
Neurological Manifestations
Symptoms evolved subacutely in all patients; 40% were
wheelchair bound at 6 months after symptom onset.
Three patients (all women) were initially assigned a
psychiatric diagnosis (adjustment disorder or conversion disorder). Neurological symptoms and signs generally were multifocal and included (in decreasing frequency): neuropathy (n ⫽ 33; 14 sensory, 11
sensorimotor, 2 motor neuropathy, 4 polyradiculopathy, and 2 neuromyotonia), encephalopathy (n ⫽ 19;
4 limbic encephalitis), myelopathy (n ⫽ 17), encephalomyelitis with rigidity (n ⫽ 18; 5 stiff-man-like, 13
stiff-limb; 15 were women, 11 had breast carcinoma),
generalized or focal pain (n ⫽ 14), cerebellar syndrome
(n ⫽ 11), Lambert–Eaton syndrome (n ⫽ 5), myoclo-
Table 1. Demographic, Oncological, and Serological Data for 25 Male Amphiphysin Antibody–Positive Patientsa
Autoantibodies Identified
Neuronal
Amphiphysin
(titer)
Patient
No.
Age/
Race
Neoplasm
1
64/C
SCLC
WB
2
3
64/C
68/C
SCLC
SCLC
4
70
5
6
7
ANNA-1, 2, 3,
PCA-2, CRMP-5
(titer)
Muscle
Cation Channel
(nM)
AChR
(nM)/
Striational
(titer)
GAD65
(nM)/
Thyroid
(titer)
⫺
⫺
GAD 0.07
960
30,720
ANNA-1 (WB)
CRMP-5
15,360
⫺
⫺
P/Q 0.79 N 0.21
⫺
⫺
⫺
⫺
⫺
SCLC
30,720
CRMP-5 30,720
⫺
72
62
57/C
⫺
SCLC
⫺
7,680
30,720
240
CRMP-5 1,920
⫺
⫺
⫺
⫺
⫺
8
87/C
Lung massb
15,360
P/Q 0.12 N 0.21
⫺
P/Q 0.06
KC 7.93
⫺
6,400 M
6,400
⫺
⫺
⫺
⫺
GAD 0.11
9
78
SCLC
15,360
⫺
⫺
⫺
10
79
⫺
KC 4.63 N 0.05
⫺
⫺
11
68/C
SCLC
WB
⫺
⫺
⫺
12
13
58/C
80/C
3,840
3,840
⫺
⫺
⫺
⫺
14
15
16
17
18
19
69
65
69/C
54
78/A
66/C
SCLC
SCLC, rectal
carcinoma
Melanoma
SCLC
⫺
SCLC
SCLC
⫺
ANNA-1 3,840
CRMP-5
15,360
⫺
⫺
1,920
3,840
15,360
30,720
30,720
3,840
⫺
⫺
ANNA-1 15,360
ANNA-1 15,360
ANNA-1 960
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
GAD 0.05
⫺
GAD 0.12
⫺
⫺
20
65
SCLC
WB
53/C
⫺
3,840
AChR
0.14
⫺
GAD 0.04
21
ANNA-1 120
CRMP-5 7,680
ANNA-1 15,360
22
67/SA
SCLC
7,680
CRMP-5 3,840
23
63
SCLC
240
ANNA-1 7,680
24
70/C
SCLC
61,440
⫺
P/Q 0.06 N 0.26
AChR 0.12
⫺
25
56/C
SCLC
61,440
⫺
N 0.10
240
⫺
CRMP-5 (WB)
⫺
P/Q 2.9 N 0.28
⫺
N 0.30
N 0.20
⫺
⫺
⫺
AChR 0.18
N 0.06 P/Q 1.03
P/Q 0.08
AChR 0.11
⫺
⫺
⫺
⫺
⫺
GAD 0.05
AChR
0.32 Str
7,680
⫺
GAD 8.03
Tg 400
M 1600
⫺
Race: C ⫽ Caucasian (white); A ⫽ Arabic; SA ⫽ South American. Neoplasm: SCLC ⫽ small–cell lung carcinoma. Antibodies: WB ⫽ Western
blot; PCA ⫽ Purkinje cell cytoplasmic; GAD ⫽ glutamic acid decarboxylase-65; Tg ⫽ thyroglobulin; M ⫽ thyroid microsomal (or thyroperoxidase [TPO]); KC ⫽ voltage-gated potassium channel; ANNA ⫽ antineuronal nuclear; muscle AChR ⫽ nicotinic (␣1) receptor; neuronal
AChR ⫽ ganglionic nicotinic (␣3) receptor; normal values: ⱕ0.02nM for GAD65, P/Q or N-type calcium channel, KC, neuronal and muscle
AChR antibodies; ⬍1:120 for neuronal nuclear and cytoplasmic autoantibodies; ⬍1:60 for striational autoantibodies.
a
Patients lacking clinical information not listed.
Refused investigation/lost to follow-up.
b
Pittock et al: Amphiphysin Autoimmunity
99
Table 2. Summary of Neurological and Other Clinical Abnormalities for 25 Male Amphiphysin Antibody–Positive Patientsa
Neurological Manifestations
Patient
No.
Stiffness/
Rigidity/
Spasm
Axial
Limb
1
⫺
⫺
2
3
⫺
⫺
4
Encephalopathyb
Other
Neurological/
Nonneurological Disorders
Cerebellar
PN
Spinal Cord
⫹
⫹
S
⫺
Constipation
⫺
⫹
⫺
L
⫺
⫺
⫺
SM
⫺
⫹
⫺
⫺
⫺
⫹
⫺
⫺
5
6
7
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫹
L
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
8
⫺
⫺
⫺
⫺
⫺
⫺
9
⫺
⫺
⫺
⫺
M
⫺
10
⫺
⫺
⫹
⫺
NM
⫹
11
⫺
⫺
⫺
⫹
M
⫺
LES
Buttock myoclonus, spinal
myoclonus
SIADH, orthostatism, optic
neuritis
Dysphagia, dysgeusia, LES
⫺
Nonkinesogenic choreoathetosis, SIADH
Myoclonus on initial presentation
Truncal ataxia without appendicular ataxia
Buttock myoclonus, pruritus, facial sweating, muscle biopsy: myositis
DVT and rash
12
13
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
S
⫺
⫺
LES
14
15
16
17
18
19
⫺
⫺
⫺
⫺
⫺
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫹aphasia
⫺
⫺
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
S
S
S
⫺
⫹
⫺
⫺
⫺
⫺
⫺
20
⫺
⫺
⫺
⫺
S
⫺
Low back pain
SIADH
⫺
DM-type 1
Dizziness, constipation
Asymmetric myoclonus UE
⬎ LE
Autonomic dysfunction
21
⫺
⫺
⫺
⫺
S
⫺
22
⫺
⫺
⫺
⫺
⫺
⫺
23
⫺
⫺
⫺
⫺
S
⫺
24
SMS
SMS
⫺
⫺
⫺
⫺
25
⫺
⫺
⫹
⫹
⫺
⫺
⫺
Constipation, diplopia, nocturia and urgency
Optic neuritis/retinitis, dysgeusia, proximal leg weakness, generalized pain
Ptosis, chorea, orofacial dyskinesia, UE allodynia
Diaphragmatic spasms necessitated mechanical ventilation
Oculomotor dysfunction
SMS ⫽ stiff-man syndrome; LE ⫽ lower extremity; UE ⫽ upper extremity; L ⫽ limbic encephalitis (patients had signal abnormalities in the
limbic/mesial temporal areas and/or EEG abnormalities in the temporal lobes); PN ⫽ peripheral neuropathy; S ⫽ sensory neuronopathy;
NM ⫽ neuromyotonia; M ⫽ motor neuronopathy; DVT ⫽ deep venous thrombosis; LES ⫽ Lambert-Eaton syndrome; SIADH ⫽ syndrome
of inappropriate antidiuretic hormone secretion; DM ⫽ diabetes mellitus.
a
Patients lacking clinical information not listed.
“Encephalopathy” indicates patients with subacute delirium, cognitive dysfunction, psychiatric disorders, or confusion.
b
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Table 3. Demographic, Oncological, and Serological Data for 38 Female Amphiphysin-IgG Positive Patientsa
Autoantibodies Identified
Neuronal
Patient
No.
Age/
Race
Neoplasm
Amphiphysin
(titer)
26
27
28
29
30
31
32
33
34
35
36
71C
51
68/C
65/C
65/C
69/C
48/C
64
70/C
67/C
50/C
Breast
Breast
Breast
Breast
SCLC
Leiomyomata uteri
Breast
SCLC
⫺
NSCLC,
Lung mass (CT)
15,360
7,680
15,360
7,680
WB
3,840
245,760
WB
WB
7,680
3,840
37
38
58/C
78/C
7,680
3,840
⫺
⫺
39
40
80/C
50/C
Breast
“Benign ovarian
mass”
Lung Mass (CT)
Breast
7,680
1,920
⫺
⫺
41
61
SCLC
3,840
⫺
42
43
44
45
46
47
48
72
69
50/C
79
46
63
69/C
Melanoma
SCLC
Breast
Lung mass (CXR)
Breast
Breast
SCLC
480
30,720
30,720
1,920
3,840
480
WB
49
50
51
52
50
73
59
71/C
Breast
Breast
Breast
Breast
7,690
15,360
15,360
1,920
53
54
55
56
57
75/C
53/C
64
62/C
71/C
Breast
SCLC
SCLC
58
59
55/C
66/C
SCLC
SCLC
60
61
62
63
74/C
48/C
54/C
77/C
–
Breast
SCLC
ANNA-1, 2, 3, PCA-2,
CRMP-5 (titer)
⫺
⫺
⫺
⫺
CRMP-5
⫺
⫺
CRMP-5
CRMP-5
⫺
CRMP-5
5,360
3,840
7,680
3,840
Cation
Channel (nM)
P/Q 0.08
⫺
⫺
⫺
P/Q 0.03
⫺
⫺
N 0.04
⫺
⫺
P/Q 0.29
AChR 0.04
⫺
N 0.04
⫺
⫺
⫺
⫺
⫺
ANNA-1 960
⫺
⫺
ANNA-1 240
CRMP-5 (WB)
⫺
⫺
⫺
–
WB
120
15,360
30,720
61,440
–
–
PCA-2 7,680
7,680
122,880
⫺
CRMP-5 30,720
PCA-2 122,880
⫺
⫺
⫺
ANNA-2 7,680
7,680
1,920
3,840
7,680
Muscle
–
P/Q 0.04
AChR 0.09
P/Q 0.39
N 0.03
⫺
⫺
⫺
⫺
P/Q 0.54
AChR (nM)/
Striational (titer)
GAD65 (nM)/
Thyroid (titer)
⫺
⫺
⫺
Str 3,840
⫺
⫺
⫺
⫺
⫺
⫺
⫺
M 6,400
⫺
⫺
⫺
⫺
⫺
GAD 0.11
Tg 100
⫺
⫺
⫺
⫺
GAD 0.17
⫺
⫺
⫺
⫺
GAD 0.05 M
6,400
Tg 102,400 M
25,600
⫺
GAD 0.21
⫺
Tg 1,600 M 6,400
AChR 0.09
⫺
⫺
⫺
⫺
⫺
⫺
⫺
GAD 0.72
⫺
⫺
⫺
⫺
–
⫺
⫺
⫺
–
–
–
KC 0.42
–
–
–
–
–
–
–
⫺
⫺
⫺
⫺
GAD 0.18
⫺
⫺
GAD 0.26 Tg 400
M 400
–
–
–
–
GAD 0.16 Tg 100
M 400
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
M100
⫺
⫺
GAD 1.90
Race: C ⫽ Caucasian (white). Neoplasm: SCLC ⫽ small–cell lung carcinoma; CXR ⫽ chest X-ray; CT ⫽ computed tomography. Antibodies:
WB ⫽ Western blot; PCA ⫽ Purkinje cell cytoplasmic; GAD ⫽ glutamic acid decarboxylase-65; Tg ⫽ thyroglobulin; M ⫽ thyroid microsomal (or thyroperoxidase [TPO]); KC ⫽ voltage-gated potassium channel; ANNA ⫽ antineuronal nuclear; muscle AChR ⫽ nicotinic (␣1)
receptor; neuronal AChR ⫽ ganglionic nicotinic (␣3) receptor; normal values: ⱕ0.02nM for GAD65, P/Q or N-type calcium channel, KC,
neuronal and muscle AChR antibodies; ⬍1:120 for neuronal nuclear and cytoplasmic autoantibodies; ⬍1:60 for striational autoantibodies.
a
Patients lacking clinical information not listed.
nus (n ⫽ 6), cranial neuropathies (n ⫽ 6), optic neuritis/retinitis (n ⫽ 3), and pruritus (n ⫽ 3).
Several of the neurological manifestations in patients
who had other autoantibodies coexisting with amphiphysin–IgG (see Tables 1 and 3) have been described
previously as characteristic accompaniments of the additional paraneoplastic autoantibodies. For example, seven
patients with sensory neuronopathy had ANNA-1, one
with neuromyotonia and one with limbic encephalitis
had K⫹-channel autoantibody, two with myelopathy
and three with optic neuritis with or without retinitis
had CRMP-5-IgG, and all five patients with Lambert–
Eaton syndrome had P/Q-type Ca2⫹-channel antibody.
Small-cell lung carcinoma was diagnosed in three of five
patients in whom the syndrome of inappropriate antidiuretic hormone secretion was documented. ANNA-1,
CRMP-5 and PCA-2 were never associated with breast
carcinoma; lung carcinoma was proven in most cases.
Pittock et al: Amphiphysin Autoimmunity
101
Table 4. Summary of Data Available for 38 Female Amphiphysin-IgG Positive Patientsa
Neurological Manifestations
Stiffness/Rigidity/
Spasm
Patient
Axial
No.
Limb
Encephalopathyb Cerebellar
⫺
⫺
⫺
PN
Spinal Cord
Other Neurological/Nonneurological Disorders
⫺
⫹
⫺
⫺
S
SM
⫹
⫹
⫾
⫺
⫺
⫺
SM
⫺
PR
⫹
⫹
⫹
⫺
⫺
4 limb asymmetric dystonia with rigidity, choreoathetosis, urinary incontinence, startle myoclonus
Generalized pruritus, inguinal and back pain
Graves disease
Subacute encephalomyeloradiculoneuritis, quadraparesis and painful opisthotonus, face, and
vaginal pain
Perioral paresthesia, subacute thyroiditis
SIADH
Hypothyroidism, constipation, encephalomyelitis
Mixed parotid tumor
LES, generalized pain and fatigue, thirst, dizziness, unusual posturing of hands, severe sensory ataxia
Truncal tremor, dystonia, equinovarus contractures, diplopia, UE/LE dysesthesia tingling
and burning, spasms elicited by touching neck
or moving UE
SIADH
GI dysmotility, episodic vertigo, emotional lability
⫺
⫺
Progressive multiple cranial neuropathies (III,
VI, VII, VIII, XII), dizziness
⫺
⫺
⫺
Loss of smell and taste
26
27
28
⫺
⫺
⫹
⫺
⫹
⫹
29
30
31
⫺
⫺
⫺
⫺
⫺
⫺
32
33
34
⫺
⫺
⫺
⫹
⫺
⫺
⫺
L
⫹
⫺
⫹
⫺
S
SM
SM
⫺
⫺
⫹
35
36
⫺
⫺
⫹
⫺
⫺
⫺
⫺
⫺
PR
SM
⫹
⫺
37
⫺
⫾
⫺
⫺
NM
⫾
38
39
⫺
⫺
⫺
⫺
⫺
⫹
⫺
⫹
S
SM
⫹
⫹
40
41
42
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫹
⫺
S
SM
⫹
⫺
⫺
43
44
45
46
SMS
SMS
⫺
⫺
SMS
SMS
⫺
⫺
⫺
⫺
⫹
⫺
⫺
⫺
⫺
⫺
SM
⫺
SM
S
⫺
⫺
⫺
⫺
47
48
49
50
51
52
53
54
55
56
57
⫹
⫺
SMS
⫺
⫺
⫺
⫺
SMS
⫺
⫹
⫺
⫹
⫺
SMS
⫺
⫹ (LE)
⫹ (LE ⬎ UE)
⫺
SMS
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫹
⫹
⫺
⫺
L
⫹
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
PR
⫺
⫺
⫺
⫺
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫺
58
59
⫺
⫺
⫹ (LE)
⫺
⫺
⫹
⫺
⫹
S
SM
⫹
⫺
60
61
62
63
⫺
⫺
⫺
⫺
⫺
⫹ (LE)
⫺
⫺
⫺
⫺
⫺
⫹
⫺
⫺
⫺
⫺
PR
⫺
⫺
⫺
⫺
⫹
⫹
⫺
⫺
⫺
⫹ delirium/
paranoia
⫺
LES, vertigo, VI nerve palsy
Thoracic radicular pain
⫺
Exaggerated startle response
⫺
Dystonia L hand, dizziness, extrapyramidal signs
Pruritus, myoclonus
⫺
Psychiatric disorder
Subacute diffuse pain, generalized weakness,
polymyalgia rheumatica
⫺
Optic neuritis/retinitis, anosmia, loss of taste,
chorea
Cranial neuropathies (III, VI, VII), incontinence
⫺
Generalized tonic clonic seizures
SMS ⫽ stiff-man syndrome; LE ⫽ lower extremity; UE ⫽ upper extremity; L ⫽ limbic encephalitis (patients had signal abnormalities in the
limbic/measial temporal areas and/or EEG abnormalities in the temporal lobes); PN ⫽ peripheral neuropathy; S ⫽ sensory neuronopathy;
PR ⫽ polyradiculopathy; NM ⫽ neuromyotonia; LES ⫽ Lambert-Eaton syndrome; SIADH ⫽ syndrome of inappropriate antidiuretic hormone secretion; GI ⫽ gastrointestinal.
a
Patients lacking clinical information not listed.
“Encephalopathy” indicates patients with subacute delirium, cognitive dysfunction, psychiatric disorders, or confusion.
b
Nineteen of the 63 patients (30%) with available
clinical information lacked coexisting autoantibodies.
Women were more frequent in this group than in patients with a coexisting autoantibody (79 vs 52%, p ⱕ
0.05), and breast carcinoma was more frequent in these
women (42 vs 18%, p ⫽ 0.03). Neurological manifestations that were significantly more frequent in patients
without accompanying autoantibodies were myelopathies (53 vs 18%, p ⬍ 0.01) and stiff-man phenomena
(58 vs 16%, p ⬍ 0.001), but these groups did not
differ significantly ( p ⬎ 0.05) in their frequency of
multifocal neurological manifestations (74 vs 73%),
cerebellar dysfunction (11 vs 20%), involvement of peripheral nerve (47 vs 50%) or neuromuscular junction
(Lambert–Eaton syndrome, 0 vs 11%), myoclonus (16
vs 7%), encephalopathy (32 vs 27%), limbic encephalitis (11 vs 5%), or stiff-man syndrome (11% vs 7%).
Patients with coexisting P/Q-type or N-type calciumchannel antibodies (n ⫽ 19) had a greater frequency of
small-cell lung carcinoma (65 vs 40%, p ⫽ 0.03) and
Lambert–Eaton syndrome (P/Q-channel antibodies
only: 38 vs 0%, p ⬍ 0.001) and a lower frequency of
stiff-man phenomena (5 vs 40%, p ⫽ 0.02) than patients without a coexisting calcium-channel antibody.
Patients with coexisting voltage-gated K⫹-channel antibodies (n ⫽ 3) were more likely to have limbic encephalitis (33.3 vs 5%, p ⬍ 0.05) or neuromyotonia
(33.3 vs 2%, p ⬍ 0.05).
Cerebrospinal Fluid Findings
Cerebrospinal fluid was abnormal in 17 (61%) of 28
patients for whom information was available: 13 had
increased white cell counts (mean, 22 ⫾ 20 cells/mL,
predominantly lymphocytes), 10 had increased protein
levels (mean, 104 ⫾ 47mg/dL) and 5 had multiple oligoclonal bands.
Magnetic Resonance Imaging
Magnetic Resonance Imaging (MRI) of the head was
considered abnormal in only 2 of 27 patients whose
scans were available for review. We excluded nonspecific T2 signal abnormalities consistent with smallvessel ischemic disease of ageing. Coexisting paraneoplastic autoantibodies in the two patients with
abnormal MRI scans have been described previously as
accompaniments of these MRI findings. Patient 7 (see
Tables 1 and 2) had T2 signal abnormality in both
medial temporal lobes consistent with his clinical presentation of limbic encephalitis; also consistent with
this neurological diagnosis, he was seropositive for neuronal voltage-gated K⫹-channel antibody (7.93nmol/L;
normal level ⱕ 0.02 nmol/L). Patient 59 (see Tables 3
and 4) had increased signal on T2-weighted and fluidattenuated inversion recovery imaging in the putamen
and caudate bilaterally, which is consistent with her
clinical evidence of autoimmune basal ganglionitis and
detection of CRMP-5-IgG in her serum.
MRI scans of cervicothoracic spine were available for
25 patients and indicated intrinsic cord abnormality in 5
patients. Two of the 20 patients without MRI abnormality in the spinal cord had signs and symptoms of a
myelopathy. All five patients with T2-weighted signal
abnormality in the spinal cord had symptomatic myelopathy. The lesion in Patient 31 involved the conus,
and the patient’s clinical course was one of a rapidly progressing predominantly motor syndrome, with spastic
quadriparesis (see Table 4). The other four patients had
longitudinally extensive signal abnormality (more than
three spinal segments); three had associated enhancement. Patient 14 (see Tables 1 and 2, Fig 2) had a rapidly progressive, predominantly motor syndrome of spastic paraparesis and required a wheelchair within 6 weeks
of onset. Patient 35 (see Tables 3 and 4) had a rapidly
progressive myeloradiculopathy requiring a wheelchair
within 3 months of onset. Patient 62 (see Tables 3 and
4) had progressive paraparesis with severe spasticity and
required a wheelchair after 18 months. Patient 30 lacked
enhancement, but had a rapidly progressive quadriparesis (see Table 3). CRMP-5-IgG, which is a recognized
“syndromic” accompaniment of paraneoplastic autoimmune myelopathy,16,22 was identified in one of these patients. No other coexisting neuronal autoantibodies were
identified in patients with myelopathy.
Therapy and Outcomes
Treatments included immunomodulation (intravenous
methylprednisolone, intravenous immunoglobulin, or
plasmapheresis) or tumor-directed therapy (radiation,
chemotherapy, and/or surgery). Thirteen patients died
during the study period, five without evidence of cancer (an autopsy was performed for only one); mean interval from symptom onset to death was 33 months.
Half of the patients in whom cancer was diagnosed received immunosuppressants, tumor-directed therapy,
or both. Their mean survival time (7 ⫾ 9 months) was
less than the survival time for patients who received no
therapy (9 ⫾ 9 months), but the difference was not
significant statistically.
A cancer was identified in 42 of the 49 patients who
were living at the end of the study period. Of the 13
who were Mayo Clinic patients, neurological improvement was documented in 9 who received tumor therapy and in 2 who received a 5-day course of intravenous methylprednisolone. No benefit was reported for
two who received plasmapheresis and one who received
intravenous immunoglobulin. Therapeutic information
was available for 11 of the 29 surviving patients not
from the Mayo clinic. Improvement was documented
in only 3 of 11 patients who received tumor therapy,
in 2 of 3 who received methylprednisolone, and in 2 of
3 who received intravenous immunoglobulin. Again,
Pittock et al: Amphiphysin Autoimmunity
103
Fig 2. Symmetric tract-restricted signal abnormality throughout thoracic cord. Sagittal (A) and axial (B) T1-weighted, postgadolinium images show enhancement (arrows). T2 axial cut also shows tract-restricted signal abnormality (C).
no improvement was observed in two who received
plasmapheresis.
Neuropathology
CASE 1: A 57-year-old man, with a history of smoking (Patient 7; see Tables 1 and 2), presented with
subacute nonkinesogenic choreoathetosis; psychosis
and hallucinations soon ensued. The patient’s serum
had a high level of K⫹-channel antibody
(7.93nmol/L) in addition to P/Q-type calciumchannel antibody (0.06nmol/L). MRI of the head
showed bilateral T2 signal abnormality in the mesial
temporal lobes. Electromyography was negative for a
defect in neuromuscular transmission. Electroencephalogram indicated paroxysmal slowing with subclinical seizure activity. Cerebrospinal fluid was abnormal
only for increased protein level (60mg/dL). Hyponatremia was interpreted as evidence for syndrome of
inappropriate anti-diuretic hormone secretion (SIADH). Chest radiograph and computed tomography
chest scan were reported normal. He had a rapid decline and died. The autopsy was limited to the brain.
Mononucleated inflammatory cells were present in
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perivascular regions, and gliosis was marked in the
hippocampus, parahippocampal cortex, amygdala, and
entorhinal cortex. The cerebellum exhibited patchy
loss of Purkinje neurons and minimal Bergman astrocytosis. No abnormality was noted in cerebral cortex,
basal ganglia, thalamus, hypothalamus, or brainstem.
CASE 2: A 70-year-old woman, with a history of
smoking (Patient 31; see Tables 3 and 4), presented
with severe facial and cranial pain. Initial evaluation
was negative, and she responded to oral prednisone.
Soon after steroid taper, the pain recurred, and she experienced development of severe neck spasm, subacute
spastic quadriparesis, nausea, and dysphagia. MRI results of the head were normal, but MRI results of the
cervicothoracic cord showed an enhancing T2 signal
abnormality extending from the conus to T11. Cerebrospinal fluid contained 50 white cells/mL (predominantly lymphocytes), 93mg/dL protein, and 3 oligoclonal bands. Computed tomography of the chest and
mammogram were negative. Electromyography and
nerve conduction studies were consistent with a diffuse
motor polyradiculopathy. The patient deteriorated rap-
Fig 3. Immunophenotyping of perivascular and parenchymal mononuclear leukocyte infiltrates (CD45⫹) in the medulla (A).
Most of the parenchymal leukocytes were CD8⫹ lymphocytes (B) or macrophages (C). B lymphocytes (CD20⫹) were restricted to
perivascular location (D). In the medial lemniscus of the pons, marked macrophage infiltration was seen (E). Scattered microglia
and CD8⫹ lymphocytes were prominent throughout the parenchyma of the spinal cord (not shown) and dorsal root ganglia (F).
idly, becoming delirious, paranoid, and opisthotonic;
she died from aspiration pneumonia 5 months after
initial symptom onset. Notably, amphiphysin-IgG was
the only autoantibody detected in this patient’s serum.
Thorough postmortem examination did not indicate
any neoplasm other than uterine fibromyomata. The
brain (1,124gm), brainstem, and spinal cord were
mildly atrophic. The cerebellum was relatively spared,
as were the hippocampus, basal ganglia, and cerebral
cortex. Microscopic abnormalities involved primarily
the brainstem and spinal cord. Scattered nodules of activated microglia and perivascular and parenchymal
lymphocytes were prominent in the brainstem but were
most marked in the medulla and spinal cord (Fig 3A).
Lymphocytes were predominantly T-type (CD3⫹), and
most leukocytes in the parenchyma were CD8⫹ T
lymphocytes (see Fig 3B) or macrophages (see Fig 3C).
B lymphocytes (CD20⫹) were restricted to perivascular
regions (see Fig 3D). The medial lemniscus of the pons
contained a mild perivascular infiltrate with aggregates
of CD8⫹ T cells and marked macrophage infiltration
(see Fig 3E). The leptomeninges (not shown) were
thickened throughout and contained scattered CD8⫹
T lymphocytes throughout.
The spinal cord distribution of inflammatory cells
was similar to that of the medulla. Throughout the parenchyma, diffuse microgliosis and infiltrates of CD8⫹
T lymphocyte were prominent. B lymphocytes
(CD20⫹) were prominent in perivascular regions. Pa-
renchymal CD8⫹ T lymphocytes and microglia were
abundant in dorsal root ganglia (see Fig 3F), with occasional B lymphocytes (not shown).
Discussion
Amphiphysin-IgG is a rare autoantibody. Despite early
and continued emphasis on its association with paraneoplastic stiff-limb syndromes,23–25 its associated
spectrum of neurological disorders is much broader.5– 8
This study’s review of the clinical manifestations encountered in 63 seropositive patients demonstrates that
encephalomyelitis with rigidity (or stiff-man phenomena) is present in a minority of women (39%) and
men (12%). Full criteria for a diagnosis of stiff-man
syndrome were met in only 10% of women and 4% of
men.26 Notably, 27% of our patients were seropositive
for GAD65 antibody, but in no patient did the serum
level approach the threshold value of 20nmol/L that
generally distinguishes patients with classic stiff-man
syndrome (90% seropositive) from patients with susceptibility to type 1 diabetes and related organ-specific
autoimmune disorders (generally ⱕ2nmol/L).19
It is notable that 8% of female patients initially were
thought to have a conversion disorder. In our continuing experience, it is not uncommon for women with
paraneoplastic disorders to be assigned initially a psychiatric diagnosis, in part because of the multifocal and
unusual neurological manifestations with frequently
negative laboratory testing (apart from autoimmune se-
Pittock et al: Amphiphysin Autoimmunity
105
rology) and normal neuroimaging studies. The diversity of neurological manifestations encountered in patients with amphiphysin autoimmunity may be
explained by concomitant immune responses to multiple onconeural antigens expressed in a single neoplasm.27 In this study of sera from 71 patients with
amphiphysin-IgG, 74% had one or more coexisting
neuronal nuclear or neuronal or muscle cytoplasmic or
cation channel autoantibodies. Cranial neuropathies (including optic neuritis), myelopathy, and chorea are considered syndromic for CRMP-5 autoimmunity,16,22,28
sensory neuronopathy and gastrointestinal dysmotility
are syndromic for ANNA-1,29 –31 neuromuscular hyperexcitability and autoimmune encephalitis are syndromic
for neuronal voltage-gated K⫹-channel antibody,32,33
and Lambert–Eaton syndrome for neuronal voltagegated P/Q-type calcium channel autoantibody.34,35
In this study, only one third of patients had isolated
amphiphysin-IgG. Notably, these patients were more
likely to be women with breast cancer and to have stiffman phenomena or myelopathies compared with
amphiphysin-IgG seropositive patients with coexisting
autoantibodies. The clinical presentation, spinal fluid
findings, and imaging characteristics of paraneoplastic
myelopathies are similar for both amphiphysin-IgG–
and CRMP5-IgG–associated disorders (B. M. Keegan,
S. J. Pittock, V. A. Lennon, unpublished observations).
Presentations are generally subacute with predominantly
motor involvement. The spinal fluid usually is mildly
pleocytic with an increased protein level. MRI results of
the spinal cord may be normal or show longitudinally
extensive T2 signal change, with or without enhancement.
Despite the widespread distribution of amphiphysin
immunoreactivity throughout the central and peripheral nervous systems, individual patients often present
with symptoms and signs restricted to a certain level of
the neuraxis. Contemporary immunological principles
suggest that an inflammatory outcome in the central
nervous system reflects local reactivation of antigenspecific cytotoxic CD8⫹ T cells generated in lymph
nodes draining a neoplasm. These cells have the potential to kill neurons targeted by surface display of peptide fragments, derived in the case of amphiphysin
from a cytoplasmic protein, in the context of upregulated MHC class 1 molecules.17 Different types of neurons may differ in their capacity to upregulate MHC
class 1 in response to the local cytokine milieu, or in the
repertoire of potentially antigenic peptide fragments that
is generated by the subunit composition of the particular
neuron’s upregulated immunoproteosome.
Our neuropathological observations in a patient without additional marker autoantibodies support a pathogenic role for amphiphysin peptide-specific cytotoxic
CD8⫹ T lymphocytes in the neurological manifestations
of amphiphysin autoimmunity. These lymphocytes were
more evident in the parenchyma than in perivascular re-
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gions, and they were in proximity to neurons.
T-lymphocyte infiltration, and accompanying microglial
activation, was most marked in the brainstem, spinal
cord, and dorsal root ganglia. The histopathological appearance of the pons’ medial lemniscus and the tractrestricted imaging abnormalities in the spinal cord are
evidence of an anatomically restricted immune response.
Recently reported neuropathological findings in another patient with “stiff-person syndrome” attributed
to amphiphysin autoimmunity also indicated a predominance of cytotoxic T cells throughout the brainstem and spinal cord parenchyma.36 We have noted
similar immunopathological findings (diffuse infiltration by CD8⫹ T lymphocytes, axonal loss, and gliosis
in the brainstem and descending spinal cord tracts) in
a patient with ANNA-2 autoimmunity associated
with breast carcinoma.37 Early initiation of therapies
directed against cytotoxic T lymphocytes or against
proinflammatory cytokines may benefit patients with
inflammatory paraneoplastic autoimmunity.
An important conclusion of our study is that targeting of multiple autoantigens may contribute to
the multifocal neurological manifestations encountered in individual patients with paraneoplastic
autoimmunity. The coexistence of multiple paraneoplastic autoantibody markers implies that the neurological presentation reflects targeting of peptides
derived from more than one neuron-specific protein. The autoantibody profiles that emerge from systematic serological screening for neuronal nuclear and
cytoplasmic autoantibodies (by a streamlined immunostaining protocol15,16 complemented by Western
blot analysis of complex staining patterns) and neuronal and muscle plasma membrane–directed autoantibodies (by radioimmunoprecipitation assays18,19,35)
are highly sensitive in predicting a specific cancer type.
These autoantibody profiles also are yielding insight into
potential immune effector mechanisms that may be the
cause of complex multifocal neurological presentations
in patients with paraneoplastic autoimmunity.
We thank our Mayo Clinic neurologist colleagues and many physician colleagues outside Mayo Clinic who provided clinical correlative data for these patients, and T. Kryzer, E. Posthumus, and A.
Maixner for excellent technical support.
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