Paraneoplastic Neurologic Syndromes

Question 1

Percentage of patients with paraneoplastic symptoms without known history of cancer

Answer 1

Up to 60%

Question 2

CSF findings in PNS

Answer 2

• elevated protein concentration (most often, 50–100 mg/dL),
• mild lymphocytic pleocytosis (10–100 cells/mm3),
• intrathecal synthesis of immunoglobulins,
• and/or the presence of oligoclonal bands.

These findings are not diagnostic of PNSs but rather reflect an inflammatory reaction.

Specific antineuronal antibodies are found in higher concentration in the CSF than in serum, suggesting intrathecal synthesis.

Question 3

Tests that should be done when PNS is suspected

Answer 3

• Computed tomography (CT) of the chest, abdomen, and pelvis
• 2-fluorodeoxy-d-glucose positron emission tomography (FDG-PET)
• mammogram
• testicular ultrasound
• serum and CSF tumor markers

Question 4

Should paraneoplastic antibodies tested in serum or CSF?

Answer 4

The existence of antibodies in serum and CSF varies across paraneoplastic disorders.

Antibodies against intracellular antigens (most classical paraneoplastic/onconeuronal antibodies) are almost always detectable in serum. It is rare to find these antibodies in CSF when they are not detected in serum.

Antibodies to cell-surface or synaptic proteins (those that associate with encephalitis with or without a cancer association)
For these antibodies, it is particularly important to test both serum and CSF.

** Some antibodies (e.g., against LGI1) are best detected in serum, with CSF showing lower sensitivity

Question 5

Paraneoplastic syndrome diagnostic criteria

Answer 5

** when tumor found but not consistent with phenotype or antibody, additional testing by a research laboratory to demonstrate that the relevant antigen is expressed by tumor cells

Question 6

Antibodies associated with paraneoplastic syndromes and the commonly found cancers

Answer 6

https://www.uptodate.com/contents/image?imageKey=NEURO%2F135170&topicKey=NEURO%2F5188&search=paraneoplastic%20syndromes&rank=1~150&source=see_link

Question 7

Classification of antibodies in PNS

Answer 7

1) against intracellural neuronal proteins (classic or onconeuronal)
2) against neuronal cell surface or synaptic proteins

Question 8

High-Risk Antibodies (>70% Associated With Cancer)

Answer 8

Question 9

Intermediate risk antibodies

Answer 9

Question 10

High risk neurologic phenotypes for paraneoplastic syndrome

Answer 10

• Encephalomyelitis
• Limbic encephalitis
• Rapidly progressive cerebellar syndrome
• Opsoclonus-myoclonus
• Sensory neuronopathy
• Gastrointestinal pseudo-obstruction (enteric neuropathy)
• Lambert-Eaton myasthenic syndrome

Question 11

Intermediate risk neurologic phenotypes for paraneoplastic syndrome

Answer 11

• Encephalitis (other than limbic)
• Brainstem encephalitis
• Morvan syndrome
• Isolated myelopathy
• Stiff-person syndrome
• Paraneoplastic polyradiculoneuropathy

Question 12

Paraneoplastic cerebellar degeneration:
1) most common cancer and antibody found

2) What causes symptoms?

3) Imaging

Answer 12

1)
anti-Yo –> breast and gynecologic cancers (mainly ovarian)

Anti-Tr and anti-mGluR1 antibodies –> Hodgkin disease

voltage-gated calcium channel (VGCC) antibodies –> PCD in patients with LEMS –> SCLC

Other antibodies associated with PCD are anti-CRMP5 (CV2), anti-Hu, anti- Ri, anti-Ma1, anti-ANNA3, anti-PCA2, and ZIC antibodies; patients with these antibodies often develop PCD along with symptoms secondary to involvement of other areas of the central nervous system

2) loss of Purkinje cells in the cerebellum

3) In advanced stages significant cerebellar atrophy

Question 13

Paraneoplastic cerebellar degeneration: treatment and prognosis

Answer 13

Treatment – As most antibodies are directed against intracellular proteins, which implies cytotoxic T cell mechanisms, the use of cyclophosphamide over plasma exchange or IVIG is preferred.

The prognosis in individuals with anti-Hu and anti-Yo is more likely to be worse, whereas it may be more favorable in those with anti-TR, anti-Ri, anti-mGluR1 and anti-CRMP5.

Question 14

Paraneoplastic encephamomyelitis: most common cancer and antibodies associated

Answer 14

EM almost always associates with SCLC with Hu or CRMP5 antibodies

Question 15

Paraneoplastic encephalomyelitis definition

Answer 15

The term encephalomyelitis should be used only in patients with clinical dysfunction at multiple sites of the nervous system, including also peripheral involvement

Included is one or more of the following conditions:
1) focal cortical encephalitis
2) limbic encephalitis
3) brainstem encephalitis
4) cerebellar dysfunction
5) myelitis
6) autonomic dysfunction (orthostatic hypotension, hypertension, gastroparesis, abnormal sweating, and neurogenic bladder or impotence)
7) peripheral nerve involvement

These additional areas of involvement should be included in the description of the phenotype, for example, EM with dorsal root ganglionitis or sensory neuronopathy or EM with peripheral neuropathy.

Question 16

Definite autoimmune limbic encephalitis: diagnostic criteria

Answer 16

Question 17

Paraneoplastic limbic (μεταιχμιακή) encephalitis: imaging

Answer 17

In most patients with paraneoplastic limbic encephalitis, lesions are seen in the mesial temporal lobes, sometimes bilaterally, or on T2-weighted or FLAIR MRI studies, with or without enhancement on T1-weighted images.

The lesions are not usually associated with mass effect, but mild edema may occur

It may be difficult to distinguish this lesion from a low-grade, infiltrative tumor.
In some cases, brain biopsy may be necessary to make the correct diagnosis.

Question 18

Young males with limbic-diencephalic-brainstem encephalitis: which cancer and antibodies should be considered

Answer 18

Ma2 antibodies with underlying testicular tumor

Question 19

Which antibodies should be tested in young women with encephalitis and which is the most common associated cancer

Answer 19

anti-NMDAR encephalitis

Anti–Nmethyl d-aspartate (NMDA) receptor encephalitis presents typically in young women with psychiatric symptoms and memory problems that are followed by seizures, unresponsiveness, autonomic instability, hypoventilation, and dyskinesias.
Psychiatric symptoms are often prominent and can
lead to misdiagnosis of a primary psychiatric disorder.

the presence of an associated tumor highly depends on age and sex.

Children of both sexes and young adult men rarely have
tumors but women aged between 18 and 35 years often have an ovarian teratoma, with frequencies ranging between 35% and 50%.

Question 20

Anti-NMDAR encephalitis: diagnostic criteria

Answer 20

Question 21

Immunomodulatory therapy for autoimmune encephalitis
(including NMDA)

Answer 21

A T cell-mediated mechanism is likely in cases of classic paraneoplastic encephalitis associated with antibodies against intracellular neuronal proteins (eg, anti-Hu, anti-Ri).
Such high-risk onconeuronal antibodies are not considered to be directly pathogenic.
Rather, damage is mediated by cytotoxic T cells and can result in irreversible neuronal degeneration

https://www.uptodate.com/contents/image?imageKey=NEURO%2F142786&topicKey=NEURO%2F15759&search=nmda%20encephalitis&rank=1~150&source=see_link

Question 22

Paraneoplastic opsoclonus-myoclonus: most common cancer and antibodies associated

Answer 22

Paraneoplastic OMS in adults frequently associates with SCLC or breast cancer.

20-40% is associated with cancer

Patients with breast cancer and paraneoplastic OMS usually have Ri antibodies

Question 23

Opsoclonus-myoclonus clinical findings

Answer 23

Opsoclonus-myoclonus syndrome is characterized by involuntary, high-frequency, chaotic multidirectional saccadic movements without intersaccadic pauses, and nonrhythmic action myoclonus, often involving the trunk, limbs, and head.

Additional features include cerebellar involvement (dysarthria and trunk ataxia) and encephalopathy (ranging from confusion to coma).

Question 24

Paraneoplastic opsoclonus-myoclonus: treatment

Answer 24

POM is one of the most treatment-responsive PNSs, especially when treated early.
Occasionally, complete resolution of the syndrome is achieved with corticosteroids.
Good results are also seen with IVIG, plasmapheresis, rituximab, and treatment of the underlying cancer.

Question 25

Paraneoplastic isolated myelopathy: clinical findings, most common cancer and antibodies associated

Answer 25

Isolated myelopathy as a paraneoplastic manifestation of cancer may have a variable clinical evolution and usually presents with longitudinally extensive, symmetric, tract or gray-matter specific abnormalities in MRI studies.

It is mainly associated with breast and lung carcinomas, and with CV2/CRMP5 and amphiphysin antibodies.

However, patients may not have neuronal antibodies, and in these cases, the possibility of a paraneoplastic origin should be considered when MRI is suggestive, and there are no alternative diagnoses.

Question 26

Stiff-person syndrome: most common cancer and antibodies associated

Answer 26

Paraneoplastic SPS is mostly associated with amphiphysin antibodies and breast cancer.

** Although some patients with anti–GAD65-associated SPS may have cancer, a paraneoplastic etiology should not be considered unless GAD65 is found expressed by the tumor cells.

Question 27

Stiff person syndrome: clinical findings

Answer 27

1) classic SPS (70 to 80 percent)
truncal stiffness, generalized rigidity, and frequent muscle spasms, resulting in an awkward, wide-based gait.
Signs and symptoms which are characteristic include a prodrome of stiffness and rigidity in axial muscles, slow progression of stiffness resulting in impairment of ambulation, fixed deformity of the spine and pronounced lordosis, and the presence of superimposed episodic spasms that are precipitated by sudden movement, noise, or emotional upset

2) partial SPS (10 to 15 percent)
most often presenting as a stiff-limb syndrome in which patients have marked difficulty with ambulation due to stiffness and lack of mobility affecting one limb, generally a leg, although other localized forms may occur

3) other more uncommon forms, including a paraneoplastic SPS variant and progressive encephalomyelitis with rigidity and myoclonus (PERM).

++ Paroxysmal autonomic dysfunction has been described and may result in sudden death, possibly related to sudden apnea and respiratory arrest from diaphragmatic spasm, impaired respiratory function, and severe respiratory muscle rigidity.
Esophageal dysmotility and swallowing difficulties may lead to aspiration.
Specific phobias may occur, and anxiety may further exacerbate muscle stiffness or may trigger spasms.

Question 28

Stiff person syndrome: diagnosis

Answer 28

The diagnosis is based upon the presence of characteristic clinical features. Muscle hardening to a board-like sensation is probably the most specific clinical observation.
The presence of the following features are generally considered necessary for making the diagnosis:

• Stiffness in the axial and limb muscles resulting in impairment of ambulation
• Presence of superimposed episodic spasms that are precipitated by sudden movement, noise, or emotional upset
• A positive therapeutic response to oral diazepam or findings of continuous motor-unit activity on EMG that are abolished by intravenous diazepam
• Absence of other neurologic disorders that may explain the clinical features

When present, anti-GAD antibodies support the diagnosis; however, these antibodies may be absent in up to one-third of patients.
In addition, in patients with characteristic clinical findings, anti-GAD antibodies, and a positive response to diazepam, the diagnosis can be made without an EMG, although such electrodiagnostic studies and a clinical response to diazepam can provide additional support for the diagnosis

Question 29

Are anti-GAD antibodies positive in paraneoplastic Stiff person syndrome?

Answer 29

Usually no!
Their absence should increase suspicion for underlying cancer

Question 30

Stiff person syndrome management

Answer 30

Question 31

Morvan syndrome: clinical findings, most common cancer and antibodies associated

Answer 31

Peripheral nerve hyperexcitability (neuromyotonia) along with encephalopathy characterized by
* behavioral change
* hallucinations
* dysautonomia
* sleep disorders, especially agrypnia excitata

Malignant thymoma is the tumor more commonly associated with Morvan syndrome, frequently accompanied by myasthenia gravis.

Morvan syndrome is almost always associated with CASPR2 antibodies, sometimes with concurrent LGI1 and netrin 1 receptor antibodies

Question 32

Paraneoplastic sensory neuronopathy clinical findings and most common antibodies associated

Answer 32

Subacute and asymmetric onset of paresthesias that gradually progress to diffuse sensory loss.
They may also have painful dysesthesias.
Sensory gait ataxia can occur in advanced stages or as the only complaint

sometimes accompanied by motor symptoms due to additional involvement of motor nerve roots of peripheral nerves

The most frequent antibodies are Hu, followed by CV2/CRMP5 and antiamphiphysin

Question 33

Paraneoplastic Lambert Eaton myasthenic syndrome: clinical findings, most common cancer and antibodies associated

Answer 33

Progressive development of proximal muscle weakness that usually starts in the lower limbs and follows with involvement of the upper limbs, distal muscles, and finally the ocular and bulbar muscles.

About 90% of patients have symptoms of autonomic dysfunction, which is a hallmark of LEMS, including dry mouth, erectile dysfunction, and constipation.

In addition to muscle weakness and dysautonomia, patients have decreased or absent muscle reflexes, which improve after repeat exercise or maximal voluntary contraction.

Antibodies against P/Q type voltage-gated calcium channels (VGCCs) are present in nearly 90% of the patients, although their detection is not needed for the diagnosis.
These antibodies occur similarly in the paraneoplastic and nonparaneoplastic forms of the disease.

Conversely, antiglial nuclear antibodies (or SOX1 antibodies) are strongly associated with SCLC or paraneoplastic syndromes associated with SCLC

Question 34

Paraneoplastic polyradiculoneuropathies: clinical findings, most common cancer and antibodies associated

Answer 34

Typically with axonal pattern and often present with concurrent CNS involvement.
Pain, dysautonomia, and distribution (symmetric or asymmetric) are variable.

The most frequent antibodies are CV2/CRMP5, amphiphysin, and PCA-2/ microtubule-associated protein 1B, usually in the context of SCLC, or breast cancer

Question 35

Paraneoplastic Gastrointestinal Pseudo-obstruction clinical findings and most common antibodies associated

Answer 35

This term applies to a clinical picture characterized by recurrent episodes of abdominal pain, distension, constipation, and/or vomiting, without evidence of mechanical obstruction.
An abnormal gastric emptying or small bowel manometry confirms the diagnosis.

Gastrointestinal pseudo-obstruction is due to a myenteric plexus dysfunction and may occur along with other features of autonomic involvement, SNN, or EM.

The identification of Hu antibodies suggests a paraneoplastic origin

Question 36

Anti LGI1 encephalitis clinical findings and most common cancer/ antibodies associated

Answer 36

• memory disturbances
• confusion
• faciobrachial dystonic seizures!!

Patients may also develop hyponatremia and REM sleep behavior disorder.
Some patients present with rapidly progressive cognitive decline without signs of encephalitis in CSF or on MRI

MRI usually shows findings typical of limbic encephalitis (eg, medial temporal lobe hyperintensity)
CSF may show pleocytosis but is often normal or only shows oligoclonal bands.

Approximately 5 percent of cases are associated with tumors
the most common associated tumor is thymoma

The associated antibodies target the LGI1 protein

Treatment with immunomodulatory therapy results in substantial clinical improvement in 70 to 80 percent of patients
Early initiation of immunomodulatory therapy in patients with faciobrachial dystonic seizures may prevent the development of cognitive impairment and improve long-term outcomes

Question 37

Paraneoplastic neurologic syndromes differential diagnosis

Answer 37

https://cdn-links.lww.com/permalink/nxi/a/nxi_2021_07_16_honnorat_2020037648_sdc1.pdf

(Link from Updated Diagnostic Criteria for Paraneoplastic
Neurologic Syndromes)