AAN - Teaching Course - 2023 Attendee

Educational Course „Autoimmune Neurology: Paraneoplastic“
Neuropathological findings and

implications for diagnosis
Romana Höftberger
Division of Neuropathology and Neurochemistry, Department of
Neurology, Medical University of Vienna
romana.hoeftberger@meduniwien.ac.at
75th Annual Meeting - AAN – American Academy of Neurology

April 22 – 27, 2023
1
Disclosures
speaker´s honoraria from Novartis, Biogen and Sanofi-Aventis GmbH
Romana Höftberger
Division for Neuropathology and Neurochemistry, Department of Neurology
2
77-year-old female patient
suspected myasthenia gravis due to bulbar symptoms, difficulty in

swallowing
Pyridostigmine and IVIG; no response
Romana Höftberger
CT: lung tumor – biospy: adenocarcinoma of lung
Serum and CSF were sent for antibody-testing
Line Assay
Tissue-based Assay Patient control
Ma2
Ma1
Ma antibody positive Ma-positive

Romana Höftberger
patient developed progressive dysphagia and tetraparesis and somnolence
She died one day after transfer to oncology department
Diagnosis: Ma-antibody-associated brainstem encephalitis
Romana Höftberger
HLADR Division for Neuropathology and Neurochemistry, Department of Neurology
Macroscopic brain investigation
6
High-risk antibodies (>70% associated with cancer)
An#body Associated tumor Syndrome
Hu (ANNA1) SCLC, others encephalomyeli;s, brainstem-
encephali;s, LE, PCD, sensory
neuronopathy
Yo (PCA1) gynecological tu, mammary cerebellar degenera;on
Ri (ANNA2) mammary, SCLC brainstem enceph., opsoclonus
Tr (DNER) Hodgkin´s lymphoma cerebellar degenera;on
CV2/ CRMP5 SCLC, thymoma, others encephalomyeli;s, uvei;s, sensory
neuropathy
Ma-1/2 tes;cular cancer, NSCLC limbic, diencephalon, brainstem-
encephali;s
Amphiphysin mammary, SCLC s;ff-person syndrome, encephalomyel.,
sens. neuronopath.
SOX1 SCLC LEMS w/wo cerebellar syndrome
PCA2 (MAP1B) SCLC, NSCLC, mammary PCD, encephalomyeli;s, neuropathy
KLHL11 Tes;cular cancer brainstem/cerebellar syndrome
Romana Höftberger
Graus et al Neurol Neuroimmunol Neuroinflamm 2021
Abteilung für Neuropathologie und Neurochemie 7
severe retrograde axonal degeneration normal spinal cord
of posterior white columns proprioceptive and tactile sensations
Dorsal root ganglion with T-cell-infiltra;on; CD3 Wanschitz et al, Neurology 1997
Graus et al 1985 encephali;s, LE, PCD, sensory
neuronopathy
tumor
- ganglion
+
immune-
-
system
Hu Hu
Romana Höftberger
neuronopathy
Medulla oblongata
CD8: T-cells
microglia; HLADR 0,5x
Romana Höftberger
12
neuronopathy
Gastrointestinal pseudoobstruction
Immunohistochemistry for Hu in normal gut

Chronic gastrointestinal pseudo-obstruction; 75-year old patient with
Hu-antibodies, weight loss of 20 kg within 1 year
symptoms:
achalasia, nausea and early
satiety
chronic constipation
weight loss
abdominal distension
CT abdomen: dilated sigma

and rectum
With courtesy of Dr. Ung, LKH Steyr
Romana Höftberger
Neuropathology in PNS
High-risk syndromes associate with cancer even if antibodies are negative
(1) Sensory neuronopathy

(2) Chronic gastrointestinal pseudoobstuction
(3) Subacute cerebellar degeneration
(4) Limbic encephalitis
(5) Encephalomyelitis
(6) Opsoclonus-myoclonus
(7) Lambert-Eaton myasthenic syndrome

Romana Höftberger
neuronopathy
neuropathy
encephali;s
sens. neuronopath.
Romana Höftberger
PCD with Yo-antibodies
Neuropathology points towards a T cell mediated pathogenesis
HE
irreversible neuronal cell loss
limited response to
immuntherapy
IgG: neurons CD8: T-cells HLA-DR: microglia
Aboul-Enein et al, 2008; Schubert et al, Acta Neuropath 2014 Winklehner et al N2, 2022
Immunopathology - pathomechanisms
Paraneoplastic cerebellar degeneration with Yo-antibodies
cerebellum-infiltra;ng T-cells secre;ng IFNγ
upregula;on of MHC class I

GranB
direct killing by an;gen-specific CD8 T cells

pSTAT1
OLYMPUS VS200 ASW 3.2.1
pSTAT1: phosporylated signal transducer

and ac;vator of transcrip;on
Winklehner et al Nn2, 2022
Neuropathology in PNS
High-risk syndromes associate with cancer even if antibodies are negative
(1) Sensory neuronopathy

(2) Chronic gastrointestinal pseudoobstuction
(3) Subacute cerebellar degeneration
(4) Limbic encephalitis
(5) Encephalomyelitis
(6) Opsoclonus-myoclonus
(7) Lambert-Eaton myasthenic syndrome

Romana Höftberger
Lambert-Eaton myasthenic syndrome
up to 90% paraneoplastic (SCLC)
85-95% are associated with anti-P/Q-

type voltage gated calcium channel
antibodies (P/Q-VGCC)
Clinical presentation:
proximal weakness, general fatigue, dry mouth,
slurred speech, double vision, droopy eyelids,
neck weakness, constipation
about 2% of P/Q-VGCC+ patients develop cerebellar ataxia

with or without LEMS
about 50% of patients with P/Q-VGCC+ PCD and tumor can be stabilized with
immunotherapy
non-paraneoplastic patients respond better to immunotherapy

Graus et al, Neurology 2002; Mitoma et al, Int J Mol Sci 2020
Romana Höftberger
Paraneoplas#c cerebellar degenera#on with P/Q-type VGCC abs
Calbindin; Purkinje cell loss with Bergmann gliosis
Winklehner et al Neurol Neuroimmunol Neuroinflamm, 2022

Romana Höftberger
21
Paraneoplastic cerebellar degeneration
associated with anti-P/Q-type VGCC antibodies
VGCC downregulation
IgG deposition in neuropil of molecular layer of

cerebellar cortex
Ca2+ dysregulation (calbindin red.)
cell stress (GRP78 upregulation )
IgG
antibodies cause altered synaptic transmission that results in calcium

dysregulation, cell stress and ends up in Purkinje cell death
Winklehner et al Neurol Neuroimmunol Neuroinflamm, 2022
neuronopathy
neuropathy
encephali;s
sens. neuronopath.

Romana Höftberger
49-year-old female pa#ent
Nov. 2021: SCLC, metasta;c
Treatment with chemotherapy and checkpoint inhibitor therapy (PDL1 inhibitor; tecentriq)
April 2022: grand mal seizures, progressive encephalopathy with dizziness, personality change,
disoriented, gait disturbance, visual hallucina;on, delirious
An#body tes#ng:
Serum and CSF: SOX1 and GABA(B)R posi;ve

24
with courtesy of Dr. Jelinek, Dr. Löcker and Dr. Dworan, Klinik Penzing
49-year-old female pa#ent
Nov. 2021: SCLC, metasta;c
Treatment with chemotherapy and checkpoint inhibitor therapy (PDL1 inhibitor; tecentriq)
April 2022: grand mal seizures, progressive encephalopathy with dizziness, personality change,
disoriented, gait disturbance, visual hallucina;on, delirious
Tecentriq was stopped
An#body tes#ng: IVIG and steroids were started
Serum and CSF: SOX1 and GABA(B)R posi;ve 3 weeks later:
Romana Höftberger
25
with courtesy of Dr. Jelinek, Dr. Löcker and Dr. Dworan, Klinik Penzing
Immunological mechanisms of PNS are tightly linked to
immunity directed against tumor cells
PNS in the era of cancer immunotherapy
tumors protect themselves from immune attack with expression of PD-L1
x activation of T cells
PDL1
Immune checkpoint inhibitors (ICI)

Romana Höftberger
1-3% of pa;ents treated with ICI develop neurological complica;ons
– 2/3 neuromuscular system (myosi;s, myasthenia gravis, neuri;s..)
– 1/3 meningi;s, encephali#s, demyelina;on, myeli;s
about 50% of encephali;s pa;ents are an;body-posi;ve, most frequently intracellular

an#bodies: Ma2 and Hu
Romana Höftberger
Vogrig et al, J Neurol 2022;
Marini et al Neurology 2021
Summary
1.  High-risk antibodies are associated with irreversible neuronal
cell death -> poor response to immuntherapy
2.  Pathogenesis: aberrant expression of neuronal antigens in

carcinomas or disrupted immune regulation in hematological
tumors (thymoma, Hodgkin´s lymphoma) are responsible for
the loss of self-tolerance
3.  Immune checkpoint inhibitor therapy can induce neurological

adverse events (1-3%), which provides a unique window into the
role of CTLA-4, PD1 and PD-L1 in the development of PNS
4.  Neuropathology strongly depends on the targeted antigen and

may vary from T-cell dominated inflammation (intracellular
antigens) to IgG deposition, altered synaptic trasmission, cell
stress and cell death (neuronal surface)
Romana Höftberger
Thank you for your attention
Romana Höftberger
email: romana.hoeftberger@meduniwien.ac.at
Division of Neuropathology and Neurochemistry

Department of Neurology, Medical University of Vienna
Romana Höftberger
29

AAN - Teaching Course - 2023 Attendee

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Educational Course „Autoimmune Neurology: Paraneoplastic“

Neuropathological findings and

75th Annual Meeting - AAN – American Academy of Neurology

speaker´s honoraria from Novartis, Biogen and Sanofi-Aventis GmbH

suspected myasthenia gravis due to bulbar symptoms, difficulty in

Pyridostigmine and IVIG; no response

Ma antibody positive Ma-positive

She died one day after transfer to oncology department

Diagnosis: Ma-antibody-associated brainstem encephalitis

Immunohistochemistry for Hu in normal gut

CT abdomen: dilated sigma

With courtesy of Dr. Ung, LKH Steyr

High-risk syndromes associate with cancer even if antibodies are negative

(1) Sensory neuronopathy

Graus et al Neurol Neuroimmunol Neuroinﬂamm 2021

irreversible neuronal cell loss

cerebellum-inﬁltra;ng T-cells secre;ng IFNγ

upregula;on of MHC class I

direct killing by an;gen-speciﬁc CD8 T cells

pSTAT1: phosporylated signal transducer

High-risk syndromes associate with cancer even if antibodies are negative

(1) Sensory neuronopathy

Graus et al Neurol Neuroimmunol Neuroinﬂamm 2021

85-95% are associated with anti-P/Q-

about 2% of P/Q-VGCC+ patients develop cerebellar ataxia

non-paraneoplastic patients respond better to immunotherapy

Calbindin; Purkinje cell loss with Bergmann gliosis

Winklehner et al Neurol Neuroimmunol Neuroinﬂamm, 2022

IgG deposition in neuropil of molecular layer of

Ca2+ dysregulation (calbindin red.)

cell stress (GRP78 upregulation )

antibodies cause altered synaptic transmission that results in calcium

Division for Neuropathology and Neurochemistry, Department of Neurology

tumors protect themselves from immune attack with expression of PD-L1

Immune checkpoint inhibitors (ICI)

about 50% of encephali;s pa;ents are an;body-posi;ve, most frequently intracellular

2. Pathogenesis: aberrant expression of neuronal antigens in

3. Immune checkpoint inhibitor therapy can induce neurological

4. Neuropathology strongly depends on the targeted antigen and

Division of Neuropathology and Neurochemistry

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2.  Pathogenesis: aberrant expression of neuronal antigens in

3.  Immune checkpoint inhibitor therapy can induce neurological

4.  Neuropathology strongly depends on the targeted antigen and