CASE-BASED PEARLS AND

ERRORS IN DIAGNOSING
EMERGING AUTOIMMUNE PERIPHERAL
NERVE AND MUSCLE CONDITIONS
Divyanshu Dubey, MD
Associate Professor of Neurology, Laboratory Medicine & Pathology
Neuroimmunology laboratory
Mayo Clinic, Rochester, MN

©2023 Mayo Foundation for Medical Education and Research | WF2517487-1

DISCLOSURES

• KLHL11 patent licensed as a marker of neurological autoimmunity

and testicular germ cell tumor
• Patent pending for LUZP4 and Cavin-4 as a marker of neurological
autoimmunity
• Consulted for UCB, Immunovant, Argenx, Arialys and Astellas.
All compensation for consulting activities is paid directly to Mayo Clinic
• Received funding from the DOD for germ cell tumor immunoprofiling
(CA210208) and inflammatory neuropathy autoantibody
identification/validation (PR220430)

©2023 Mayo Foundation for Medical Education and Research | WF2517487-2

CASE 1: 64-YEAR-OLD MAN PRESENTING WITH
PROGRESSIVE ORTHOPNEA AND BENDOPNEA
• Mild weakness involving the right arm
• Soon after right arm weakness he also developed orthopnea and
bendopnea (shortness of breath when bent over)
• He also reported 2-year history rapid eye movement behavioral disorder
• History of vocal cord paralysis 11 years ago
• Neurological examination:
• Right deltoid fasciculations
• Mild right deltoid and external rotation weakness
• Deep tendon reflexes were brisk
• MRI brain and spine were unremarkable

©2023 Mayo Foundation for Medical Education and Research | WF2517487-3

 Patient diaphragm Normal diaphragm
Fat layer

Serratus anterior

External oblique

Expiration Internal oblique

Parietal layer
0.09 cm 0.22 cm
Muscular layer
Diaphragm thickness Maximal
Visceral layer diaphragm
thickness

Inspiration
1.77 cm
Maximal
0.09 cm diaphragm
Maximal diaphragm thickness thickness

Diaphragmatic ultrasound. Diaphragm of the patient on the left did not expand during the inspiration phase. Maximal
diaphragm thickness was 0.09 cm (normal > 0.15 cm) when both inspiring and expiring. In contrast to normal subject,
significant diaphragmatic thickness was seen.
Thakolwiboon, Klein, Dubey. Mayo Clin Proc. In press

©2023 Mayo Foundation for Medical Education and Research | WF2517487-4

ARS

WHAT IS THE DIAGNOSIS?

A. CRMP5 IgG seropositive brachial plexopathy/phrenic neuropathy

B. Amyotrophic later sclerosis
C. IgLON5 IgG associated disease
D. HMGCR IgG seropositive necrotizing autoimmune myopathy
E. Musk IgG seropositive myasthenia gravis

©2023 Mayo Foundation for Medical Education and Research | WF2517487-5

IgLON5 IGG ASSOCIATED DISEASE

• IgLON5 autoimmunity was first described in association with

RBD and sleep apnea
• Recent studies have reported MND-like phenotype with IgLON5 IgG
• Clues to the diagnosis:
• History of vocal cord paresis
• REM behavioral disorder
• The protracted course over 11 years has been reported in other cases as well,
supporting markedly slower disease progression compared to other
autoimmune disorders
• Immunotherapy refractoriness is also commonly seen, potentially due to
connection between this autoantibody-mediated process and
neurodegeneration
Thakolwiboon, Klein, Dubey. Mayo Clin Proc. In press, Sabater et al. Lancet Neurol. 2014
Sista SR et al. J Neurol. 2022, Nissen et al. Front Neurol. 2019, Landa et al. Ann Neurol. 2020

©2023 Mayo Foundation for Medical Education and Research | WF2517487-6

CASE 2: 61-YEAR-OLD MAN WITH GAIT IMBALANCE

• Progressive gait imbalance over 15 years, and worsening balance

with head movement
• Clinical examination:
• Gaze-evoked nystagmus
• Hypoactive vestibulo-ocular reflex and compensatory saccade
("catch-up" saccade to reach the target)
• Bilaterally, diminished vibration sense distally upper and lower limbs,
• Wide-based ataxic gait
• Family history unremarkable

©2023 Mayo Foundation for Medical Education and Research | WF2517487-7

DIAGNOSTIC WORK UP
EMG/NCS: severe sensory neuronopathy,
and a chronic motor length-dependent neuropathy

MRI brain: Cerebellar atrophy

Paraneoplastic immunoassay (Recombx®):
Hu/ANNA1 IgG positive, titer 1:100 (normal<1:100)

Tissue immunofluorescence assay: negative

©2023 Mayo Foundation for Medical Education and Research | WF2517487-8
ARS

WHAT IS THE UNDERLYING DIAGNOSIS?

A. Friedrich's ataxia
B. Paraneoplastic Neurologic syndrome
(sensory ganglionopathy and cerebellar ataxia)
C. Vitamin B12 deficiency
D. CANVAS syndrome
E. Neurofascin 155 IgG4 associated combined
central and peripheral demyelinating disease

©2023 Mayo Foundation for Medical Education and Research | WF2517487-9

CEREBELLAR ATAXIA, NEUROPATHY, AND VESTIBULAR
AREFLEXIA SYNDROME (CANVAS)

• Genetic testing revealed – biallelic AAGGG repeat expansion in the

RFC1 gene
• CANVAS: adult-onset disorder characterized by vestibulopathy
with cerebellar ataxia and sensory neuronopathy
• All patients have impairment of the oculocephalic reflex
(doll's eyes or visually enhanced vestibulo-ocular reflex)
• Other common symptoms: dry cough, autonomic dysfunction
• Clues to the diagnosis:
• Vestibular areflexia/impaired oculocephalic reflex
• Late onset slowly progressive disease cerebellar ataxia
• Sensory neuronopathy
Migliaccio et al. Brain. 2004, Budhram et al. J Neurol Sci. 2020

©2023 Mayo Foundation for Medical Education and Research | WF2517487-10

ASSAYS OF
PARANEOPLASTIC Immunodot sera
(n=5,300)

ANTIBODY TESTING
Negative Positive
• Clinical data collected for: (n=4,979; 93.8%) (n=330; 93.8%)

• 58 IFA positive immunodot + cases Excluded (n=16):

• GAD65, recoverin, titin
• 90 IFA negative immunodot + cases
Indirect immunofluorescence
(n=314)
• All patients with IFA confirmed presented
clinical symptoms classically described
Negative Positive
with the identified antibody.

• The clinical presentation of most (84%)
of the IFA negative cases was
incompatible with the antibody identified
by immunodots.
Western blot or cell-based assay Western blot or cell-based assay
(according to antibody type) (according to antibody type)
Using recombinant protein to rule using recombinant protein to
out (n=211; 67.2%) confirm (n=103; 32.8%)

Redrawn from: Déchelotte B, Et al. Neurol Neuroimmunol Neuroinflamm. 2020

©2023 Mayo Foundation for Medical Education and Research | WF2517487-11

CASE 3: 50-YEAR-OLD MAN WITH NUMBNESS,
DYSARTHRIA, VERTIGO
• Six months of gradually worsening "tingling numbness" in the distal arms & legs
• Bilateral upper and lower extremity weakness (foot drop)
• Slurred speech
• Urinary retention
• Exam:
• dysarthric speech
• weak in all four extremities, distal>proximal
• decreased to pinprick in all four extremities in a stocking/glove distribution
• decrease in position and vibration sensation as well in all four extremities
• Absent reflexes
• Wheelchair bound

©2023 Mayo Foundation for Medical Education and Research | WF2517487-12

• NCS/EMG: Nerve
conduction velocities were
slowed, and motor
amplitudes were decreased;
the distal latencies were T2 T1-Gd
quite prolonged
• Lumbar puncture : protein:
282 mg/dl,
• Density is moderately decreased
total nucleated cells: • Decrease is multifocal
10 cells/mcl • Selective decrease in large fibers
• Sub-perineurial edema

©2023 Mayo Foundation for Medical Education and Research | WF2517487-13

ARS

WHAT IS THE UNDERLYING DIAGNOSIS?

A. POEMS (Polyneuropathy, Organomegaly, Endocrinopathy,

Monoclonal protein, Skin changes) syndrome
B. MAG IgM associated DADS (distal acquired demyelinating sensory) neuropathy
C. CRMP5 associated paraneoplastic polyradiculoneuropathy
D. CANOMAD (chronic ataxic neuropathy with ophthalmoplegia,
IgM paraprotein, cold agglutinins, and disialosyl antibodies)
E. Neurofascin 155 IgG4 associated autoimmune nodopathy

©2023 Mayo Foundation for Medical Education and Research | WF2517487-14

NEUROFASCIN 155-IGG4 LIVE CELL BASED ASSAY (FACS)

Negative Control Case

IBI=1.26 IBI=102.6

©2023 Mayo Foundation for Medical Education and Research | WF2517487-15

NF155 IGG4 POSITIVE VS NEGATIVE CIDP CASES

• Sensory ataxic (OR: 10.79, 95% CI: 5.24–22.22)

• Tremor (OR: 6.71, 95% CI: 3.37–13.39)
• Response to IVIg (OR: 0.09, 95% CI: 0.02–0.42

• Marked symmetric hypertrophy of the cervical and lumbosacral nerve roots/plexuses

• Others features - distal>proximal weakness, cranial neuropathies, autonomic dysfunction,
neuropathic pain
Hu…Zhao. Brain Behav, 2018
Ogata & Yamasaki. Clinical and Experimental Neuroimmunology, 2018
Shahar…Dubey. Neurology. 2021

©2023 Mayo Foundation for Medical Education and Research | WF2517487-16

EUROPEAN ACADEMY OF NEUROLOGY/PERIPHERAL NERVE SOCIETY GUIDELINE ON DIAGNOSIS
AND TREATMENT OF CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY:
REPORT OF A JOINT TASK FORCE – SECOND REVISION

Disorders not classified as CIDP

• Autoimmune nodopathies: Antibodies against nodal-paranodal cell-adhesion molecules (contactin-1

[CNTN1], neurofascin-155 [NF155], contactin-associated protein 1 [Caspr1], and neurofascin isoforms
NF140/186) have been discovered in a small subset of patients fulfilling 2010 EFNS/PNS criteria for CIDP…

• Patients with these antibodies often have specific clinical characteristics…

• The TF proposed to name these conditions “auto-immune nodopathies” and not to regard them as CIDP
variants because they have distinct clinical features, no overt inflammation or macrophage-mediated
demyelination and do poorly respond to CIDP treatment, IVIg in particular.

Van den Bergh et al. J Peripheral Nervous Sys, 2021

©2023 Mayo Foundation for Medical Education and Research | WF2517487-17

CASE 4: 58-YEAR-OLD WOMEN WITH DIPLOPIA
AND PTOSIS
• Metastatic melanoma, treatment with pembrolizumab
• Before 4th dose, for the last 3-5 days:
• Diplopia on extreme right gaze
• Ptosis
• Exam:
• ptosis, R adduction deficit
• Neck flexion weakness
• Mild bilateral hip flexion weakness
• Patient progressed over 3 days: proximal weakness and shortness of breath

©2023 Mayo Foundation for Medical Education and Research | WF2517487-18

ARS

WHAT IS THE UNDERLYING DIAGNOSIS?

A. ICI related polyradiculoneuropathy

B. ICI related myasthenia gravis
C. ICI related myositis
D. Critical illness neuromyopathy
E. ICI related Lambert Eaton myasthenic syndrome

©2023 Mayo Foundation for Medical Education and Research | WF2517487-19

ICI RELATED MYOSITIS AND MYOCARDITIS

• EMG: diffuse myopathic process which is affecting cranial muscles

as well. No NMJ defect.
• Labs: CK 3224 U/L (N:39-308), Trop T: 1237 ng/L (N <15)
• Cardiac MRI: myocardial hyperenhancement compatible with
inflammation from acute myocarditis
•  ICI discontinued, received IVMP and high dose oral steroids
•  Clear improvement, persistent diplopia and minimal weakness

©2023 Mayo Foundation for Medical Education and Research | WF2517487-20

ICI RELATED MYOSITIS
• Myopathy presentations:
• 42% had oculo-bulbar involvement; 58%
generalized
• 42% had respiratory compromise
• 38% had dysphagia
• 33% had co-existing myocarditis; irAEs
of other systems often co-exist
• 70% of patients have elevated CK (45% >1000
IU/I)  lower in ocular/oculo-bulbar presentation

• >50% of patients tested had imaging abnormalities

(MRI or PET)

• Biopsy: Necrotic and regenerating fibers in

multifocal clusters

• In comparison to idiopathic NAM:

• More ocular involvement
• More myocarditis
• Lower CK
Sechi et al, Neurology 2020; Shelly et al, Brain Com 2020; Suzuki et al , Neurology 2017, Dubey et al. Ann Neurol. 2020.

©2023 Mayo Foundation for Medical Education and Research | WF2517487-21

67-YEAR-OLD WITH PROGRESSIVE WEAKNESS AND
DYSPHAGIA S/P ICI FOR RIGHT EYE MELANOMA

• Muscle biopsy: Inflammatory infiltrate and nemaline rods

• Treated: 3 days IVMP, prednisone taper
(60 mg daily and tapering to 20 mg daily over 5 weeks and then off )
• Follow up visit: Complete resolution of symptoms, normal strength Dubey et al. Annals of Neurology. 2020

©2023 Mayo Foundation for Medical Education and Research | WF2517487-22

 ICI RELATED NEUROPATHIES
NEUROENDOCRINE TUMOR
25
75
6 10
Modified Rankin Scale
NON-NEUROENDOCRINE TUMOR
6
Sensory Neuronopathy 12
Polyradiculoneuropathy
Length-dependent neuropathy 44
Phrenic neuropathy 19
Brachial plexopathy All irNeuropathies
Multiple mononeuropathies associated with
19 neuroendocrine
tumor were
onconeural antibody

INCAT disability scale

5 8 seropositive
4
6
3
4 Neuroendocrine
2 Non-neuroendocrine
1 2
0 0
Before ICI Post-ICI at Post-IST + Before ICI Post-ICI at Post-IST +
Nadir ICI Nadir ICI
Cessation Cessation Chompoopong… Dubey. JNNP. 2021
Sechi...Zekeridou et al, Neurology. 2020

©2023 Mayo Foundation for Medical Education and Research | WF2517487-23

SITC MANAGEMENT RECOMMENDATIONS
Grade CTCAE Description Management

1 Mild symptoms • Hold ICI

• Consider permanent discontinuation of ICI

2 Moderate symptoms; • Hold ICI

limiting instrumental ADL • 0.5–1.0 mg/kg/day methylprednisolone PO or IV
• Consider permanent discontinuation of ICI

3 Severe symptoms; • Permanently discontinue ICI

limiting self-care ADL • Start 1–2 mg/kg/day methylprednisolone
equivalents IV and prophylactic antibiotics
• Consider plasmapheresis if no improvement or
symptoms worsen after 3 days
4 Life-threatening • Same as Grade 3
consequences; urgent • Contact ICU
intervention indicated
SITC guidelines, 2017

©2023 Mayo Foundation for Medical Education and Research | WF2517487-24

CASE 5: 40-YEAR-OLD MAN WITH MYALGIAS
AND WAVE-LIKE MUSCLE CONTRACTION

©2023 Mayo Foundation for Medical Education and Research | WF2517487-25

ARS

WHAT IS THE UNDERLYING DIAGNOSIS?

A. Morvan syndrome
B. Isaac syndrome
C. Myasthenia gravis
D. Immune mediated rippling muscle disease
E. Cramp fasciculation syndrome

©2023 Mayo Foundation for Medical Education and Research | WF2517487-26

ARS

WHICH OF FOLLOWING ANTIBODIES IS A

SPECIFIC BIOMARKER OF THIS DISEASE?
A. CASPR2 IgG
B. CASPR1 IgG
C. Titin IgG
D. Caveolin 3 (CAV3) IgG
E. CAVIN4 IgG

©2023 Mayo Foundation for Medical Education and Research | WF2517487-27

IDENTIFICATION AND VALIDATION OF Cavin-4 IgG

8 of 10 iRMD cases were

cavin-4 IgG+

Dubey et al. JAMA Neurol. 2022

©2023 Mayo Foundation for Medical Education and Research | WF2517487-28

 MUSCLE PATHOLOGY
Caveolin-3 Cavin-4 Dystophin-C
Control
iRMD

Depletion of cavin-4 expression in iRMD

patient muscle biopsies suggests the
potential role of this autoantigen in
hRMD

disease pathogenesis.

Dubey et al. JAMA Neurol. 2022

©2023 Mayo Foundation for Medical Education and Research | WF2517487-29

iRMD ASSOCIATED WITH THYMOMA AND Cavin-4 IgG

Juliette Svahn et al. Neurol Neuroimmunol Neuroinflamm 2023;10:e200068

©2023 Mayo Foundation for Medical Education and Research | WF2517487-30

TAKE HOME POINTS

• Utility of antibody evaluations continues grow in various presentations

of autoimmune neuromuscular disorders
• New antibodies are being discovered nearly every year
• Clinical and electrodiagnostic phenotypic characterization should guide
serological studies
• A negative antibody panel does not rule out an autoimmune diagnosis
• If autoantibody result is positive but the clinical course/phenotype is
atypical one must consider false positive result (assay, Ig subtype)
or limited antibody specificity (striational antibody)

©2023 Mayo Foundation for Medical Education and Research | WF2517487-31

THANK
YOU!
QUESTIONS
dubey.divyanshu@mayo.edu

©2023 Mayo Foundation for Medical Education and Research | WF2517487-32