a detailed notes and table for Paraneoplastic syndromes

1. I. Introduction
A. Neoplastic cells can produce substances that **alter** the physiology of **multiple** systems
B. Paraneoplastic syndromes are disorders associated with tumors but **not directly related to mass effects or
invasion**
C. Tumors of neuroendocrine origin, such as **small-cell lung carcinoma (SCLC)** and **carcinoids**, commonly cause
paraneoplastic syndromes
D. **Prevalence** of paraneoplastic syndromes is **higher** than is generally appreciated
II. Clinical Manifestations of Paraneoplastic Syndromes
A. **Signs, symptoms, and metabolic alterations** associated with paraneoplastic disorders are **easily overlooked**
in the context of a malignancy and its treatment
B. Atypical clinical manifestations in a patient with cancer should prompt consideration of a **paraneoplastic
syndrome**
III. Endocrine Paraneoplastic Syndromes
A. **Etiology**
1. Hormones can be produced from **eutopic** or **ectopic** sources
2. Ectopic expression involves **abnormal regulation** of hormone production and **peptide processing**
3. **Genetic rearrangements** and **cellular dedifferentiation** can cause ectopic hormone production
B. **Molecular Mechanisms of Ectopic Hormone Production**
1. Rare instances involve genetic rearrangements, translocations, and somatic genetic rearrangements
2. Cellular dedifferentiation is a common cause, leading to gene expression at earlier developmental stages
C. **Pathway of Differentiation** in Small-Cell Lung Carcinoma (SCLC)
1. Neuroendocrine phenotype in SCLC is influenced by the **hASH1 transcription factor**
2. Abnormal expression of hASH1 and other developmental transcription factors link cell proliferation and
differentiation
D. **Clinical Significance** of Ectopic Hormone Production
1. Excessive and unregulated hormone production can lead to **substantial morbidity** and complicate the cancer
treatment plan
2. Paraneoplastic endocrinopathies may be a **presenting clinical feature** of underlying malignancy and prompt the
search for an unrecognized tumor
IV. Common Paraneoplastic Endocrine Syndromes
A. **Hypercalcemia**
1. Overproduction of **PTHrP** and other factors
B. **Hyponatremia**
1. Excess **vasopressin** production

2. C. **Cushing's syndrome**
1. Ectopic **ACTH** production
V. Other Paraneoplastic Endocrine Syndromes (**Table 93-1**)
A. Various paraneoplastic endocrine syndromes have been described
B. Recurring syndromes include:
1. Hypercalcemia caused by overproduction of **PTHrP** and other factors
2. Hyponatremia resulting from excess **vasopressin** production
3. Cushing's syndrome due to ectopic **ACTH** production
VI. Conclusion
Paraneoplastic syndromes associated with neoplastic cells can cause alterations in hormonal and hematologic systems.
Ectopic hormone production, driven by genetic rearrangements or cellular dedifferentiation, can lead to clinical
manifestations and complications. Recognizing the signs and symptoms of paraneoplastic syndromes is crucial for timely
diagnosis and appropriate management in patients with cancer. Common endocrine paraneoplastic synd
I. Etiology
- **Humoral hypercalcemia of malignancy (HHM)** occurs in up to 20% of cancer patients.
- Most common in **lung, head and neck, skin, esophageal, breast, genitourinary tract cancers, multiple myeloma,
lymphomas,** and their metastases.
- Overproduction of **PTHrP** is the most common cause of HHM.
- Bone metastases can produce **PTHrP and other chemokines,** leading to local osteolysis and hypercalcemia.
- **PTHrP** plays a role in tumor initiation and progression through pro-survival and chemokine pathways.
- **PTHrP** is structurally similar to **PTH** and binds to the **PTH receptor.**
- **PTHrP** has physiological roles in **skeletal development** and cellular **proliferation and differentiation** in
other tissues.
- Induction of **PTHrP** in malignancy is stimulated by **hedgehog pathways, Gli transcription factors, TGF-β,**
oncogene mutations, and loss of tumor suppressor **p53.**
- Excess production of **1,25-dihydroxyvitamin D** and tumor-mediated production of **osteolytic cytokines and
inflammatory mediators** are other causes of HHM.
II. Clinical Manifestations
- Typical presentation: known malignancy with **hypercalcemia** detected on routine laboratory tests.
- Hypercalcemia can be an initial presenting feature of malignancy.
- Symptoms may include **fatigue, mental status changes, polyuria, dehydration,** and **nephrolithiasis.**
- Electrocardiographic changes, such as **shortened ST segments and QT intervals, bundle branch blocks, and
bradyarrhythmias,** may occur.
- Features favoring HHM over primary hyperparathyroidism: known malignancy, recent onset of hypercalcemia, very
high serum calcium levels.

3. - Hypercalcemia caused by **PTHrP** is accompanied by **hypercalciuria, hypophosphatemia, and metabolic
alkalosis.**
- Measurement of **PTH** helps exclude primary hyperparathyroidism, as **PTH levels should be suppressed in
HHM.**
- Elevated **PTHrP** level confirms the diagnosis (present in approximately 80% of hypercalcemic patients with
cancer).
- Increased **1,25-dihydroxyvitamin D** levels may be observed in lymphoma patients.
III. Treatment
- Management starts with removing excess calcium from the diet, medications, or IV solutions.
- **Saline rehydration** to dilute serum calcium and promote calciuresis.
- **Forced diuresis** with loop diuretics may enhance calcium excretion.
- **Oral phosphorus supplementation** until serum phosphorus levels normalize.
- **Bisphosphonates** (e.g., pamidronate, zoledronate, etidronate) to reduce serum calcium and suppress calcium
release.
- **Denosumab** as a decoy receptor for RANK ligand to mitigate osteoclast stimulation.
- **Cinacalcet** to stimulate calcium-sensing receptors and suppress PTH secretion in select cases.
- **Glucocorticoid treatment** for hypercalcemia associated with lymphomas, multiple myeloma, or leukemia.
- **Dialysis** in severe hypercalcemia when other treatments are insufficient or too slow.
- Calcitonin and mithramycin have limited utility compared to other available agents.
Note:
Refer to Chapter 410 for additional information on PTHRP.
I. Etiology
- **Ectopic vasopressin** production by tumors is a common cause of **syndrome of inappropriate antidiuretic
hormone (SIADH).**
- Nonneoplastic conditions, such as **CNS trauma, infections, and medications**, can also cause SIADH.
- Prolonged production of excessive vasopressin can lead to **resetting of osmostat controlling thirst** and
hypothalamic vasopressin secretion.
- **Neuroendocrine tumors** like SCLC and carcinoids are the most common sources of ectopic vasopressin production.
- Ectopic vasopressin production also occurs in other forms of lung cancer, CNS lesions, head and neck cancer, and
genitourinary, gastrointestinal, and ovarian cancers.
- Mechanism of vasopressin gene activation in these tumors is unknown, but concomitant expression of the adjacent
oxytocin gene suggests derepression of this locus.
II. Clinical Manifestations

4. - Most patients with ectopic vasopressin secretion are **asymptomatic**, with hyponatremia detected on routine
testing.
- Symptoms may include **weakness, lethargy, nausea, confusion, depressed mental status, and seizures**.
- Severity of symptoms reflects the rapidity and severity of hyponatremia.
- Hyponatremia develops slowly but can be exacerbated by IV fluids or new medications.
III. Diagnosis
- Diagnostic features of ectopic vasopressin production are similar to other causes of SIADH.
- Hyponatremia and reduced serum osmolality occur with **inappropriately normal or increased urine osmolality**.
- Urine sodium excretion is normal or increased, except in the presence of volume depletion.
- Other causes of hyponatremia, renal/adrenal/thyroid insufficiency, physiological vasopressin stimulation, adaptive
circulatory mechanisms, and medications should be considered.
- Vasopressin measurements are usually not necessary for diagnosis.
IV. Treatment
- Correction of ectopic vasopressin-associated SIADH should be **gradual**, unless altered mental status or seizure risk
is present.
- Treatment of the underlying malignancy may reduce vasopressin production, but the response is often slow.
- **Fluid restriction** to less than urine output, plus insensible losses, can partially correct hyponatremia.
- Strict monitoring of fluid intake is essential for effective fluid restriction.
- **Demeclocycline** can be used to inhibit vasopressin action on the renal tubules, but its onset of action is relatively
slow.
- **Vaptan** class of drugs (e.g., conivaptan, tolvaptan) inhibits vasopressin receptors and can be used in combination
with fluid restriction.
- Severe hyponatremia or mental status changes may require treatment with **hypertonic or normal saline infusion**
together with furosemide.
- Sodium correction should be slow to prevent rapid fluid shifts and the development of central pontine myelinolysis.
Note: Refer to Chapter 53 for additional information on Ectopic Vasopressin and SIADH.
Sure! Here's a table summarizing the treatment options for Ectopic Vasopressin-Associated SIADH:

5. Treatment Dose/Regimen Mechanism of Action Side Effects
Fluid Restriction
Restrict intake to <
urine output
Reduces water intake to
correct hyponatremia
Thirst, potential
dehydration
Demeclocycline
150-300 mg orally 3-4
times daily
Inhibits vasopressin action
on renal tubules
Photosensitivity,
gastrointestinal
disturbances
Vaptan class (e.g.,
conivaptan, tolvaptan)
Varies depending on
specific drug
Inhibits vasopressin
receptors in renal
collecting ducts
Thirst, dry mouth,
increased thirst, electrolyte
imbalances
Hypertonic or Normal
Saline Infusion with
Furosemide
As determined by the
healthcare provider
Corrects severe
hyponatremia by
enhancing free water
clearance
Volume overload,
electrolyte imbalances,
renal impairment
Cushing’s Syndrome Caused by Ectopic ACTH Production
Etiology
 Ectopic ACTH production accounts for 10–20% of cases of Cushing’s syndrome.
 Neuroendocrine tumors, particularly small cell lung cancer (SCLC), are the most common causes of ectopic ACTH
production.
 Increased expression of the proopiomelanocortin (POMC) gene, which encodes adrenocorticotropic hormone
(ACTH), is the main mechanism.
 In many tumors, there is abundant but aberrant expression of the POMC gene from an internal promoter,
resulting in increased ACTH production.
 Rarely, corticotropin-releasing hormone (CRH) produced by certain tumors can cause pituitary corticotrope
hyperplasia and Cushing’s syndrome.
 Ectopic expression of various G protein–coupled receptors in adrenal nodules can also lead to ACTH-independent
Cushing’s syndrome.
Clinical Manifestations
 Patients with ectopic ACTH syndrome may exhibit less marked weight gain and centripetal fat redistribution
compared to other causes of Cushing’s syndrome.

6.  Clinical features are dominated by fluid retention and hypertension, hypokalemia, metabolic alkalosis, glucose
intolerance, and occasionally steroid psychosis.
 High levels of ACTH often cause increased pigmentation, reflecting increased activity of melanocyte-stimulating
hormone (MSH) derived from the POMC precursor peptide.
 Marked skin fragility and easy bruising may occur due to extraordinarily high glucocorticoid levels.
 Activation of renal mineralocorticoid receptors by cortisol can lead to severe hypokalemia.
 The clinical presentation of ectopic ACTH syndrome distinguishes it from other causes of Cushing’s syndrome,
such as pituitary adenomas, adrenal adenomas, and iatrogenic glucocorticoid excess.
Diagnosis
 The diagnosis of ectopic ACTH syndrome is usually made in the setting of a known malignancy.
 Urine-free cortisol levels fluctuate but are typically greater than two to four times normal, indicating
hypercortisolemia.
 Plasma ACTH levels are usually elevated (>22 pmol/L or >100 pg/mL).
 Unlike pituitary sources of ACTH, most ectopic sources do not respond to glucocorticoid suppression.
 High-dose dexamethasone suppression test (8 mg PO) fails to suppress ectopic ACTH in approximately 90% of
cases.
 Bronchial and other carcinoids may exhibit feedback regulation similar to pituitary adenomas, including
suppression by high-dose dexamethasone and ACTH responsiveness to adrenal blockade.
 Additional diagnostic procedures, such as petrosal sinus catheterization, imaging studies (CT/MRI), and special
stains, may be performed to evaluate the source of ACTH production.
 Heading Points
Etiology - Ectopic ACTH production accounts for 10–20% of Cushing’s syndrome cases.
- Neuroendocrine tumors, particularly SCLC, are the most common causes.
- Increased expression of the POMC gene leads to ectopic ACTH production.
- CRH produced by certain tumors can cause pituitary corticotrope hyperplasia
and Cushing’s syndrome.

7. Here's a
table
summarizing the information with the requested headings:
- Ectopic expression of G protein–coupled receptors can lead to ACTH-
independent Cushing’s syndrome.
Clinical
Manifestations
- Fluid retention, hypertension, hypokalemia, metabolic alkalosis, glucose
intolerance, steroid psychosis.
- Increased pigmentation, skin fragility, and severe hypokalemia.
Diagnosis - Measure urine-free cortisol levels and plasma ACTH levels.
- Ectopic ACTH sources do not respond to glucocorticoid suppression.
- High-dose dexamethasone fails to suppress ectopic ACTH in most cases.
- Bronchial and other carcinoids may exhibit feedback regulation similar to
pituitary adenomas.
- Imaging studies (CT or MRI) and specialized staining for suspected carcinoid
lesions.
- PET or octreotide scanning may identify sources of ACTH production.

8. Heading Effects Side Effects Advantages Doses Mechanism Class of Drug
Treatment
Gradual
correction Brain dehydration
Corrects
hyponatremia
Correct
gradually
- Inhibition of
vasopressin action
on renal tubules Demeclocycline
Central pontine
myelinolysis
Reduces ectopic
vasopressin
production
150-300 mg
orally 3-4
times daily
- Inhibition of
vasopressin receptors
in renal ducts Conivaptan
Combination with
fluid restriction
PO: 20-120 mg
bid
- Vasopressin
antagonist Tolvaptan
Enhanced free
water clearance IV: 10-40 mg
Hypertonic or
normal saline
Slow sodium
correction Rapid fluid shifts
Effective in
euvolemic
hyponatremia
Slow (0.5-1
meq/L per
hour) Furosemide
Development of
myelinolysis
Treatment of
underlying
malignancy
Here's a table summarizing the information with the requested headings:
Heading Effects Advantages Doses Mechanism Side Effects Class of Drug
Treatment
Reduction of
morbidity
associated
with ectopic
ACTH
syndrome
Management of
metabolic
derangements
Ketoconazole:
300-600 mg
PO bid
Inhibition of
steroid
synthesis
Depression,
personality
changes, fatigue Ketoconazole

9. Heading Effects Advantages Doses Mechanism Side Effects Class of Drug
Potential
reduction of
cortisol levels
Metyrapone:
250-500 mg
PO every 6 h
Inhibition of
steroid
synthesis
Poor wound
healing,
predisposition to
infections Metyrapone
Practical strategy
for managing
hypercortisolism
Mitotane: 3-6
g PO in four
divided doses
Decreased
cortisol
production and
secretion
Increased risk of
opportunistic
infections Mitotane
Prevention of
adrenal
insufficiency
Increased risk of
venous
thromboembolism Etomidate
Improved glucose
intolerance and
hypertension
Etomidate:
0.1-0.3
mg/kg/h IV
Inhibition of
steroid
synthesis Glucocorticoids
Rapid onset of
action,
improvement of
glucose
intolerance
Mifepristone:
200-1000 mg
PO qd
Inhibition of
glucocorticoid
and
progesterone
receptors
Poor wound
healing,
predisposition to
infections Mifepristone
Under
investigation for
future treatment
options
Neutralization
of ACTH or
blocking of
ACTH receptors
ACTH
antibodies
Selective
inhibition of
the
glucocorticoid
receptor
Glucocorticoid
receptor
inhibitors
Note: The rearranged table provides a concise overview. Please refer to the original text or
**Title: Tumor-Induced Hypoglycemia**
**I. Introduction**
- Overview of tumor-induced hypoglycemia
- Relationship between certain tumors and excessive insulin-like growth factor type II (**IGF-II**) production
**II. Tumor Types and Mechanisms**
- Mesenchymal tumors, hemangiopericytomas, hepatocellular tumors, adrenal carcinomas, and other large tumors
associated with hypoglycemia
- Role of **IGF-II precursor** in binding to insulin and IGF-I receptors

10. - Imprinting of the **IGF-II gene** on chromosome 11p15 and its biallelic expression in tumors
- Complex alterations in circulating binding proteins leading to increased **IGF-II bioavailability**
- Suppression of **growth hormone (GH)** and **insulin** by increased IGF-II, resulting in reduced **IGF binding
protein 3 (IGFBP-3)**, IGF-I, and **acid-labile subunit (ALS)**
- Displacement of IGF-II to a small circulating complex with greater access to insulin target tissues
- Impairment of **gluconeogenesis** due to tumor occupation of the liver
**III. Clinical Presentation**
- Clinical features of tumor-induced hypoglycemia
- Size of tumor and association with fasting
- Symptoms such as **sweating, tremors, palpitations, confusion, seizures, or coma**
**IV. Diagnosis**
- Diagnostic criteria: low serum glucose, suppressed insulin levels, and symptoms of hypoglycemia
- Challenges in measuring circulating IGF-II levels
- Elevated **IGF-II/IGF-I ratio** (>10:1) as a suggestive indicator
- Increased **IGF-II mRNA expression** in tumor samples
**V. Treatment and Management**
- Elimination of medications associated with hypoglycemia
- Importance of treating the underlying malignancy, if feasible, to reduce hypoglycemic episodes
- Strategies to prevent hypoglycemia: frequent meals and IV glucose, especially during sleep or fasting
- Use of **glucagon** and **glucocorticoids** to enhance glucose production
- Development of **antibodies** that inhibit IGF-II action as potential treatment options
Note: It is important to consult medical resources or healthcare professionals for accurate and up-to-date information
regarding the diagnosis and treatment of tumor-induced hypoglycemia.
**Title: Tumor-Related Endocrine Disorders**
**I. Human Chorionic Gonadotropin (hCG)**
- Composition and Production of hCG:
- hCG composed of **α and β subunits**
- Ectopic production of intact hCG occurs in **testicular embryonal tumors, germ cell tumors, extragonadal
germinomas, lung cancer, hepatoma, and pancreatic islet tumors**
- Eutopic production of hCG occurs with **trophoblastic malignancies**
- hCG α subunit production is particularly common in **lung cancer and pancreatic islet cancer**

11. - Clinical Manifestations and Diagnostic Considerations:
- High hCG levels in **men stimulate steroidogenesis and aromatase activity**, leading to **increased estrogen
production and gynecomastia**
- Clinical indicators in men: **precocious puberty or gynecomastia**
- Importance of **hCG measurement** and considering **testicular tumor or ectopic hCG production**
- Treatment Approach:
- Directed at the underlying malignancy
- Consideration of **tumor removal**
**II. Oncogenic Osteomalacia (Tumor-Induced Osteomalacia)**
- Pathophysiology and Tumor Types:
- Caused by excessive production of **fibroblast growth factor 23 (FGF23)**
- Tumor types associated with oncogenic osteomalacia: **hemangiopericytomas, fibromas, giant cell tumors**
- Also observed in patients with **sarcomas, prostate cancer, and lung cancer**
- Clinical Features and Diagnosis:
- Markedly reduced **serum phosphorus** and **renal phosphate wasting**
- Clinical presentation: **muscle weakness, bone pain, and osteomalacia**
- Normal **serum calcium** and **parathyroid hormone (PTH) levels**
- Diagnosis confirmed by **tumor resection** and subsequent resolution of symptoms
- Treatment Strategies:
- Tumor removal if feasible
- Supplementation with **phosphate and vitamin D**
- Potential use of **octreotide treatment** to reduce phosphate wasting
- Consideration of **cinacalcet** to reduce PTH-mediated phosphaturia
- Future therapies targeting FGF23 production (e.g., FGFR1) or inhibiting its action (e.g., FGF23 receptor)
**III. Consumptive Hypothyroidism**
- Development and Mechanism:
- Hypothyroidism in newborns with **hepatic hemangiomas**
- Overexpression of **type 3 deiodinase (D3)** leading to degradation and inactivation of **thyroxine (T4)** and
**triiodothyronine (T3)**
- Very high expression of D3 and consumption of thyroid hormones overwhelm the thyroid gland's rate of hormone
production
- Clinical Features and Diagnosis:
- **Low T4**, **low T3**, **high TSH**, and markedly elevated **reverse T3 (rT3)** levels
- Treatment Approach:

12. - Addressing the underlying **hemangioma**
- L-thyroxine replacement to normalize TSH levels
- Potential benefits of **steroids** and **propranolol** in inhibiting growth factor pathways stimulating D3 production
Note: Consult medical resources or healthcare professionals for accurate and up-to-date information on the diagnosis and
treatment of tumor-related endocrine disorders.
Table 1: PARANEOPLASTIC SENSORY NEURONOPATHY OR DORSAL ROOT GANGLIONOPATHY
Features Description
Sensory deficits Symmetric or asymmetric deficits
Painful dysesthesias Presence of painful abnormal sensations
Radicular pain Pain originating from the spinal nerve roots
Decreased or absent reflexes Reduced or absent reflex responses
Involvement of all modalities of
sensation
Any sensory modality can be affected, including face
and trunk
Involvement of special senses (e.g.,
taste, hearing) Impairment of taste and hearing may occur
Electrophysiologic studies - Decreased or absent sensory nerve potentials
- Normal or near-normal motor conduction velocities
Inflammatory process
Inflammatory, likely immune-mediated process
targeting dorsal root ganglia
Neuronal loss and secondary
degeneration
Loss of neurons in dorsal root ganglia and subsequent
degeneration of posterior columns of the spinal cord
Involvement of nerve roots and
peripheral nerves
Dorsal and anterior nerve roots and peripheral
nerves may be affected
Association with encephalomyelitis
and autonomic dysfunction
Often precedes or is associated with
encephalomyelitis and autonomic dysfunction
Immunologic and oncologic
associations
Hu antibodies and small cell lung cancer are
associated
Therapeutic approach
Prompt treatment of the tumor and cytotoxic T cell-
mediated mechanisms
Treatment options
Glucocorticoids may produce stabilization or
improvement
Benefit of IVIg and plasma exchange is not proven
Table 2: PARANEOPLASTIC PERIPHERAL NEUROPATHIES

13. Features Description
Development
Can occur at any time during the course of
neoplastic disease
Late-stage neuropathies
Mild to moderate sensorimotor deficits due to
axonal degeneration of unclear etiology
Concurrent neurotoxicity
Often masked by concurrent neurotoxicity from
chemotherapy and other cancer therapies
Early-stage neuropathies
Rapid progression, sometimes with a relapsing and
remitting course
Inflammatory infiltrates and axonal
loss/demyelination
Evidence of inflammatory infiltrates, axonal loss, or
demyelination
**Paraneoplastic Uveitis and Optic Neuritis with CRMP5 Antibodies**
- Paraneoplastic uveitis and optic neuritis may harbor CRMP5 antibodies.
**Paraneoplastic Retinopathies and Immune-Mediated Pathogenesis**
- Some paraneoplastic retinopathies are associated with serum antibodies that specifically react with the subset of retinal
cells undergoing degeneration, supporting an immune-mediated pathogenesis (Table 94-2).
- Paraneoplastic retinopathies rarely show substantial improvement after treatment of the tumor and immunotherapy.
- Stabilization of symptoms and partial responses to a variety of immunotherapies (glucocorticoids, plasma exchange, IVIg,
rituximab, or alemtuzumab) have been reported.
**Neuropathies Associated with Monoclonal Gammopathies**
- Diseases associated with monoclonal gammopathies such as multiple myeloma, osteosclerotic myeloma,
cryoglobulinemia, amyloidosis, Waldenström’s macroglobulinemia, or POEMS syndrome may cause neuropathy through
various mechanisms.
- Mechanisms include compression of roots and plexuses by metastasis, deposits of amyloid in peripheral nerves, or direct
interaction of abnormal immunoglobulins with peripheral nerve antigens.
- The neuropathy phenotype and likelihood of improvement with successful treatment of the gammopathy depend on the
underlying hematologic disorder.
- Neuropathies are more common with IgM gammopathies, followed by IgG and IgA.
**Vasculitis of Nerve and Muscle**

14. - Vasculitis of the nerve and muscle causes a painful symmetric or asymmetric distal axonal sensorimotor neuropathy with
variable proximal weakness.
- It predominantly affects elderly men and is associated with an elevated erythrocyte sedimentation rate and increased
CSF protein concentration.
- Small cell lung cancer (SCLC) and lymphoma are the primary tumors involved.
- Glucocorticoids and cyclophosphamide often result in neurologic improvement.
**Peripheral Nerve Hyperexcitability (Neuromyotonia or Isaacs' Syndrome)**
- Peripheral nerve hyperexcitability is characterized by spontaneous and continuous muscle fiber activity of peripheral
nerve origin.
- Clinical features include cramps, muscle twitching (fasciculations or myokymia), stiffness, delayed muscle relaxation
(pseudomyotonia), and spontaneous or evoked carpal or pedal spasms.
- Some patients may develop paresthesias and hyperhidrosis.
- Electromyogram (EMG) shows fibrillations, fasciculations, and myokymic discharges.
- CRMP5 antibodies may be present in some cases.
- Phenytoin, carbamazepine, and plasma exchange can improve symptoms.
**Guillain-Barré Syndrome and Brachial Plexitis in Hodgkin's Lymphoma**
- Guillain-Barré syndrome and brachial plexitis have occasionally been reported in patients with Hodgkin's lymphoma, but
there is no clear evidence of a paraneoplastic association.
**Paraneoplastic Autonomic Neuropathy**
- Paraneoplastic autonomic neuropathy usually develops as a component of other disorders such as Lambert-Eaton
myasthenic syndrome (LEMS) and encephalomyelitis.
- It can occur as a pure or predominantly autonomic neuropathy with cholinergic or adrenergic dysfunction.
- Complications can include gastrointestinal paresis, cardiac dysrhythmias, and postural hypotension.
- Associated tumors include SCLC, pancreatic or testicular cancer,
carcinoid tumors, and lymphoma.
- Serum Hu and CRMP5 antibodies should be sought, especially when autonomic symptoms are present.
- Autoimmune autonomic ganglionopathy is associated with antibodies to ganglionic neuronal acetylcholine receptors and
frequently occurs without cancer association.
**Other Related Disorders**

15. - Lambert-Eaton myasthenic syndrome (LEMS), myasthenia gravis, polymyositis-dermatomyositis, and immune-mediated
necrotizing myopathy are discussed in other chapters (Chap. 448 and Chap. 365).
- Immune-mediated necrotizing myopathy is characterized by myalgias, rapid progression of weakness, elevated muscle
enzymes, extensive necrosis with minimal inflammation, and complement deposits.
- Paraneoplastic visual syndromes involve the retina, uvea, and optic nerves.
- Cancer-associated retinopathy is characterized by progressive loss of vision, color perception, scotomas, and abnormal
ERG responses. It is most commonly associated with SCLC.
- Melanoma-associated retinopathy affects patients with metastatic cutaneous melanoma and presents with night
blindness and photopsias. ERG shows reduced b-waves.
- Paraneoplastic optic neuritis and uveitis can develop in association with encephalomyelitis. CRMP5 antibodies may be
present.
Sure! Here's the modified table:
Subheading Clinical Features
Diagnostic
Findings
Associated
Tumors
Antibodies Treatment
IMMUNE-
MEDIATED
NECROTIZING
MYOPATHY
Myalgias, rapid
weakness
progression,
involvement of
extremities, neck,
pharyngeal,
respiratory, and
cardiac muscles
Elevated serum
muscle enzymes,
muscle biopsy
showing
extensive
necrosis with
minimal
inflammation
and complement
deposits
May occur
without cancer
association
(e.g., statin
exposure,
connective
tissue disease,
HIV) or with
cancer
association
Antibodies against
3-hydroxy-3-
methylglutaryl-
coenzyme A
reductase
(HMGCR) or
seronegative
status
Successful treatment of
underlying tumor and
aggressive immunotherapy
(steroids, IVIg, steroid-
sparing
immunosuppressants)

16. Subheading Clinical Features
Diagnostic
Findings
Associated
Tumors
Antibodies Treatment
PARANEOPLASTIC
VISUAL
SYNDROMES
Photosensitivity,
progressive loss of
vision and color
perception, central
or ring scotomas,
night blindness,
attenuated ERG
responses
ERG shows
reduced b-waves
with normal dark
adapted a-waves
Most
commonly
associated
tumor: SCLC;
Metastatic
cutaneous
melanoma in
melanoma-
associated
retinopathy
CRMP5
antibodies in
paraneoplastic
uveitis and optic
neuritis
Stabilization of symptoms
and partial responses to
immunotherapies
(glucocorticoids, plasma
exchange, IVIg, rituximab,
or alemtuzumab) reported;
rarely show substantial
improvement after tumor
treatment
Here's the table for the additional information you provided:
Subheading Clinical Features
Diagnostic
Findings
Associated Tumors Antibodies Treatment
Paraneoplastic
Uveitis and Optic
Neuritis
Uveitis and optic
neuritis in
association with
encephalomyelitis
Presence of
CRMP5
antibodies
Various tumors,
including SCLC
CRMP5
antibodies
Immunotherapies
(glucocorticoids,
plasma exchange,
IVIg, rituximab, or
alemtuzumab)
reported; if
demyelinating
features predominate,
IVIg, plasma
exchange, or
glucocorticoids may
improve symptoms

17. Subheading Clinical Features
Diagnostic
Findings
Associated Tumors Antibodies Treatment
Paraneoplastic
Retinopathies
Specific serum
antibodies reacting
with subset of
retinal cells
undergoing
degeneration
- -
Immune-
mediated
pathogenesis
supported by
specific
antibodies
Rarely show
substantial
improvement after
tumor treatment;
stabilization of
symptoms and partial
responses to
immunotherapies
(glucocorticoids,
plasma exchange,
IVIg, rituximab, or
alemtuzumab)
reported
Guillain-Barré
Syndrome and
Brachial Plexitis
Occasional reports
in patients with
Hodgkin's
lymphoma, but
unclear
paraneoplastic
association
- Hodgkin's lymphoma - -
Neuropathy
Associated with
Monoclonal
Gammopathies
Neuropathy caused
by various
mechanisms in
diseases associated
with monoclonal
gammopathies
-
Multiple myeloma,
osteosclerotic
myeloma,
cryoglobulinemia,
amyloidosis,
Waldenström's
macroglobulinemia,
POEMS syndrome,
among others
-
Treatment depends
on the underlying
hematologic disorder
Vasculitis of
Nerve and
Muscle
Painful symmetric
or asymmetric
distal axonal
sensorimotor
neuropathy with
variable proximal
weakness
Elevated
erythrocyte
sedimentation
rate, increased
CSF protein
concentration
Small cell lung cancer
(SCLC), lymphoma
-
Glucocorticoids and
cyclophosphamide
often result in
neurologic
improvement
Peripheral Nerve
Hyperexcitability
(Neuromyotonia
or Isaacs'
Syndrome)
Spontaneous and
continuous muscle
fiber activity of
peripheral nerve
origin
EMG shows
fibrillations,
fasciculations,
myokymic
discharges
Benign and malignant
thymomas, SCLC
Caspr2
antibodies
(usually in
Morvan's
syndrome)
Phenytoin,
carbamazepine, and
plasma exchange
improve symptoms

18. Subheading Clinical Features
Diagnostic
Findings
Associated Tumors Antibodies Treatment
Paraneoplastic
Autonomic
Neuropathy
Autonomic
dysfunction,
gastrointestinal
paresis, cardiac
dysrhythmias,
postural
hypotension
Presence of Hu
and CRMP5
antibodies,
ganglionic
neuronal
acetylcholine
receptor
antibodies in
autoimmune
autonomic
ganglionopathy
Various tumors,
including SCLC,
pancreatic or
testicular cancer,
carcinoid tumors,
lymphoma
Hu and
CRMP5
antibodies,
ganglionic
neuronal
acetylcholine
receptor
antibodies
Treatment depends
on the underlying
cause and symptoms

19. ENCEPHALITIDES WITH ANTIBODIES TO CELL-SURFACE OR SYNAPTIC PROTEINS (Table 94-3)
These disorders are important for four reasons:
1. Occurrence:
- Can occur with and without tumor association
- Less frequently develop after a viral encephalitis (herpes simplex or Japanese encephalitis)
2. Age and Gender Predominance:
- Some syndromes predominate in young individuals and children
- Occurs in both men and women, with a higher incidence in young women
- Occurs in older patients of both sexes
3. Treatment and Response:
- Responds to treatment of the tumor, if found, and immunotherapy
- Immunotherapy options include glucocorticoids, IVIg, plasma exchange, rituximab, or cyclophosphamide
4. Pathogenicity:
- Antibody pathogenicity has been demonstrated in models using cultures of neurons or passive transfer of patients'
antibodies to animals
Encephalitis with N-Methyl-D-Aspartate (NMDA) Receptor Antibodies:
- Characterized by:
- Occurrence in young women and children, but can affect men and older patients of both sexes
- Symptom progression with a prodrome resembling viral process, followed by severe psychiatric symptoms, sleep
dysfunction, reduced verbal output, memory loss, seizures, decreased consciousness, abnormal movements, autonomic
instability, and frequent hypoventilation
- Monosymptomatic episodes, such as pure psychosis, may occur in about 5% of patients
- Diagnostic features:
- Intrathecal synthesis of antibodies likely by infiltrating plasma cells in the brain and meninges
- Normal brain MRI in about 65% of patients, with the remaining 35% showing mild and transient FLAIR abnormalities
affecting cortical and subcortical regions
- Tumor association:
- Detection of an associated teratoma, with higher prevalence in female patients 12 years or older
- Rare tumor detection in young male patients
- In older patients, about 20% have tumors (e.g., breast, ovary, or lung cancer)
Encephalitis with α-Amino-3-Hydroxy-5-Methylisoxazole-4-Propionic Acid (AMPA) Receptor Antibodies:
- Affects middle-aged women
- Manifests as acute limbic dysfunction or prominent psychiatric symptoms

20. - Underlying tumor in 70% of patients (lung, breast, or thymus)
- Brain MRI shows typical features of limbic encephalitis in about 50% of cases
- Neurologic relapses may occur, responsive to immunotherapy
Encephalitis with GluK2 Antibodies:
- Can affect children and adults
- Associated with rapidly progressive encephalopathy with cerebellar ataxia or cerebellitis
- Symptoms include impaired memory, altered consciousness, dyskinesias, choreoathetosis, bradykinesia, spastic
paraparesis, and intracranial hypertension in some cases
- Teratoma association observed in one patient
Encephalitis with γ-Aminobutyric Acid Type A (GABAA) Receptor Antibodies:
- Can affect children and adults
- Associated with prominent seizures and status epilepticus often requiring pharmacologically induced coma
- Brain MRI shows multifocal, asynchronous, cortical-subcortical T2/FLAIR abnormalities involving temporal and frontal
lobes, basal ganglia, and other regions
- Most patients do not have an underlying tumor, but some may have thymoma (usually of Japanese ethnicity)
Encephalitis
with γ-Aminobutyric Acid Type B (GABAB) Receptor Antibodies:
- Affects older men
- Presents as limbic encephalitis, but with a more subacute course and lower rate of tumor association
- Brain MRI often shows hippocampal, insular, and amygdala T2/FLAIR hyperintensities
- Tumor association (lung, lymphoma, and testis) in a minority of cases
Encephalitis with Contactin-Associated Protein-Like 2 (CASPR2) Antibodies:
- Affects men and women equally
- Manifests with limbic, faciobrachial dystonic seizures, and cerebellar dysfunction
- Brain MRI may show T2/FLAIR abnormalities in medial temporal lobes, frontal lobes, and cerebellum
- 20% of patients have an underlying thymoma, typically older men
Encephalitis with Leucine-Rich Glioma-Inactivated 1 (LGI1) Antibodies:
- Affects older men more frequently
- Presents as limbic encephalitis with faciobrachial dystonic seizures and hyponatremia

21. - Brain MRI often shows medial temporal lobe T2/FLAIR hyperintensities
- Underlying tumor in approximately 20% of patients (small cell lung cancer)
Encephalitis with Contactin-2 (CNTN2) Antibodies:
- Rare condition affecting both children and adults
- Presents with subacute encephalopathy, neuropsychiatric symptoms, seizures, and sometimes prominent cerebellar
ataxia
- No known tumor association
Please note that this summary is a condensed version of the information you provided, and it may not include all the
details or nuances.
Sure! Here's the table with the font size reduced to normal for the clinical features column:
Encephalitides Clinical Features Age Gender Antibody
Radiological
Findings Association Treatment
NMDA
Receptor
Antibodies
Severe psychiatric
symptoms, sleep
dysfunction,
reduced verbal
output, memory
loss, seizures,
decreased
consciousness,
abnormal
movements,
autonomic
instability, frequent
hypoventilation
Young
women
and
children,
but can
affect
men and
older
patients
of both
sexes
Both men
and
women,
with a
higher
incidence
in young
women
N-Methyl-D-
Aspartate
(NMDA) receptor
antibodies
Normal brain
MRI in about
65% of patients;
mild and
transient FLAIR
abnormalities
affecting cortical
and subcortical
regions in the
remaining 35%
Associated
teratoma,
higher
prevalence in
female
patients 12
years or
older; rare
tumor
detection in
young male
patients;
about 20% of
older
patients have
tumors (e.g.,
breast, ovary,
or lung
cancer)
Treatment of tumor
(if found) and
immunotherapy
(glucocorticoids,
IVIg, plasma
exchange,
rituximab, or
cyclophosphamide)
AMPA
Receptor
Antibodies
Acute limbic
dysfunction,
prominent
psychiatric
symptoms
Middle-
aged
women -
α-Amino-3-
Hydroxy-5-
Methylisoxazole-
4-Propionic Acid
(AMPA) receptor
antibodies
Typical features
of limbic
encephalitis in
about 50% of
cases on brain
MRI
Underlying
tumor in 70%
of patients
(lung, breast,
or thymus) Immunotherapy

22. Encephalitides Clinical Features Age Gender Antibody
Radiological
Findings Association Treatment
GluK2
Antibodies
Rapidly progressive
encephalopathy
with cerebellar
ataxia or
cerebellitis,
impaired memory,
altered
consciousness,
dyskinesias,
choreoathetosis,
bradykinesia,
spastic paraparesis,
intracranial
hypertension in
some cases
Children
and
adults - GluK2 antibodies -
Teratoma
association
observed in
one patient -
GABAA
Receptor
Antibodies
Prominent seizures,
status epilepticus
often requiring
pharmacologically
induced coma
Children
and
adults -
γ-Aminobutyric
Acid Type A
(GABAA)
receptor
antibodies
Multifocal,
asynchronous,
cortical-
subcortical
T2/FLAIR
abnormalities
involving
temporal and
frontal lobes,
basal ganglia,
and other
regions on brain
MRI
Most
patients do
not have an
underlying
tumor, but
some may
have
thymoma
(usually of
Japanese
ethnicity) Immunotherapy
GABAB
Receptor
Antibodies
Limbic encephalitis
with subacute
course, lower rate
of tumor
association
Older
men -
γ-Aminobutyric
Acid Type B
(GABAB)
receptor
antibodies
Hippocampal,
insular, and
amygdala
T2/FLAIR
hyperintensities
on brain MRI
Tumor
association
(lung,
lymphoma,
and testis) in
a minority of
cases -
CASPR2
Antibodies
Limbic encephalitis,
faciobrachial
dystonic seizures,
cerebellar
dysfunction
Men and
women -
Contactin-
Associated
Protein-Like 2
(CASPR2)
antibodies
T2/FLAIR
abnormalities in
medial temporal
lobes, frontal
lobes, and
cerebellum on
brain MRI
20% of
patients have
an
underlying
thymoma -
Note: The font size for the clinical features column has been reduced to
Here's the requested table with the provided information:

23. Encephalitides Clinical Features Age Gender Antibody
Radiological
Findings
Association Treatment
Dipeptidyl-
Peptidase-Like
Protein-6
(DPPX)
Antibodies
Preceded or
concurrent with
diarrhea, other
gastrointestinal
symptoms,
substantial weight
loss
- -
Dipeptidyl-
Peptidase-Like
Protein-6
(DPPX)
antibodies
-
B-cell neoplasms
reported in associated
cases
Treatment of
underlying
gastrointestinal
disease,
immunotherapy
Neurexin 3 Alpha
Antibodies
No distinctive
clinical features
- -
Neurexin 3
Alpha antibodies
-
Not associated with
cancer
Immunotherapy
Anti-IgLON5
Disease
Rapid eye movement
(REM) and non-
REM (NREM)
parasomnia, bulbar
symptoms, gait
abnormalities,
movement disorders,
oculomotor
dysfunction,
cognitive decline (in
some cases)
Early
60s
Equally
affects
men and
women
-
CSF and
MRI findings
are minor or
unclear
Strong association
with HLA RB110:01
and HLA-
DQB105:01, not
associated with
cancer
Poor response to
immunotherapy,
neuropathologic
findings show
neuronal
tauopathy
primarily in the
hypothalamus and
brainstem
tegmentum
Encephalitides
with Cell-Surface
or Synaptic
Protein
Antibodies
Variable clinical
features, often
respond to
immunotherapy and
tumor treatment
- -
Antibodies
against cell-
surface or
synaptic proteins
-
Treatment of tumor
(if appropriate),
progressive
escalation of
immunotherapy
(glucocorticoids,
IVIg, plasma
exchange), rituximab
or cyclophosphamide
if no response
Myelin
Oligodendrocyte
Glycoprotein
(MOG)
Antibodies
Optic neuritis,
myelitis, acute
disseminated
encephalomyelitis
(ADEM) in children
and young adults
Children
and
young
adults
-
Myelin
Oligodendrocyte
Glycoprotein
(MOG)
antibodies
- -
Immunotherapy,
relapses may
occur in 30% of
cases
Cortical
Encephalitis with
MOG Antibodies
Unilateral or bilateral
cortical encephalitis,
variable response to
treatment
- -
Myelin
Oligodendrocyte
Glycoprotein
(MOG)
antibodies
- - Immunotherapy
Please note that in some cases, the information provided was limited, and

24. Here's the revised table with diagnostic findings separated into laboratory findings and radiological findings for
Paraneoplastic Cerebellar Degeneration:
Note: Tables 94-2 and 94-3 contain further information regarding antibodies and associated tumor types in relation to
cerebellar syndromes.
Encephalitides Clinical Features Age Gender Antibody
Radiological
Findings Association Treatment
Dipeptidyl-
Peptidase-Like
Protein-6 (DPPX)
Antibodies
Preceded or
concurrent with
diarrhea, other
gastrointestinal
symptoms,
substantial weight
loss - -
Dipeptidyl-
Peptidase-Like
Protein-6 (DPPX)
antibodies -
B-cell neoplasms
reported in
associated cases
Treatment of
underlying
gastrointestinal
disease,
immunotherapy
Neurexin 3
Alpha
Antibodies
No distinctive
clinical features - -
Neurexin 3
Alpha antibodies -
Not associated
with cancer Immunotherapy
Anti-IgLON5
Disease
Rapid eye
movement (REM)
and non-REM
(NREM)
parasomnia,
bulbar symptoms,
gait abnormalities,
movement
disorders,
oculomotor
dysfunction,
cognitive decline
(in some cases)
Early
60s
Equally
affects
men
and
women -
CSF and MRI
findings are
minor or
unclear
Strong association
with HLA RB110:01
and HLA-
DQB105:01, not
associated with
cancer
Poor response to
immunotherapy,
neuropathologic
findings show
neuronal
tauopathy
primarily in the
hypothalamus
and brainstem
tegmentum
Encephalitides
with Cell-Surface
or Synaptic
Protein
Antibodies
Variable clinical
features, often
respond to
immunotherapy
and tumor
treatment - -
Antibodies
against cell-
surface or
synaptic
proteins -
Treatment of
tumor (if
appropriate),
progressive
escalation of
immunotherapy
(glucocorticoids,
IVIg, plasma
exchange),
rituximab or
cyclophosphamide
if no response
Myelin
Oligodendrocyte
Glycoprotein
(MOG)
Antibodies
Optic neuritis,
myelitis, acute
disseminated
encephalomyelitis
Children
and
young
adults -
Myelin
Oligodendrocyte
Glycoprotein
(MOG)
antibodies - -
Immunotherapy,
relapses may
occur in 30% of
cases

25. Encephalitides Clinical Features Age Gender Antibody
Radiological
Findings Association Treatment
(ADEM) in children
and young adults
Cortical
Encephalitis
with MOG
Antibodies
Unilateral or
bilateral cortical
encephalitis,
variable response
to treatment - -
Myelin
Oligodendrocyte
Glycoprotein
(MOG)
antibodies - - Immunotherapy
Here's a detailed table for Paraneoplastic Encephalomyelitis and Focal Encephalitis with Antibodies Against Intracellular
Neuronal Proteins:
Syndrome
Associated
Tumors Antibodies Clinical Features
Laboratory
Findings
Radiological
Findings Treatment
Paraneoplastic
Encephalomyelitis
Small cell
lung
cancer
(SCLC),
various
other
cancers
Hu
antibodies in
serum and
CSF
- Cortical
encephalitis:
"epilepsia partialis
continua"<br>-
Limbic encephalitis:
confusion,
depression, agitation,
short-term memory
deficit, seizures<br>-
Brainstem
encephalitis: eye
movement disorders,
cranial nerve paresis,
dysarthria, dysphagia,
gait ataxia,
autonomic
dysfunction<br>-
Cerebellar gait and
limb ataxia<br>-
Myelitis: motor and
sensory symptoms,
myoclonus, muscle
rigidity, spasms,
sphincter
dysfunction<br>-
Autonomic
dysfunction: cardiac
arrhythmias, postural
- Hu antibodies
in serum and
CSF<br>
- CRMP5
antibodies (less
frequently)<br>-
Ma proteins
antibodies<br>-
Kelch-like
protein 11
antibodies<br>-
Amphiphysin
antibodies
- MRI
abnormalities:
limbic
encephalitis
(unilateral or
bilateral medial
temporal lobe
abnormalities),
involvement of
hypothalamus,
basal ganglia, or
upper
brainstem<br>-
Variable
involvement of
different brain
regions
Treat underlying
tumor<br>
Consider
immunotherapies
aimed at cytotoxic
T-cell responses

26. Syndrome
Associated
Tumors Antibodies Clinical Features
Laboratory
Findings
Radiological
Findings Treatment
hypotension, central
hypoventilation
Focal Encephalitis
with Antibodies
Against
Intracellular
Neuronal Proteins
SCLC, other
cancers
CRMP5
antibodies
- Limbic encephalitis:
confusion,
depression, agitation,
short-term memory
deficit, seizures<br>-
Chorea, uveitis, optic
neuritis (less
frequently)
- CRMP5
antibodies
- MRI
abnormalities:
limbic
encephalitis
(unilateral or
bilateral medial
temporal lobe
abnormalities)
Treat underlying
tumor
Ma proteins
antibodies
- Limbic,
hypothalamic, and
brainstem
encephalitis<br>-
Occasionally with
cerebellar
symptoms<br>-
Hypersomnia,
cataplexy, severe
hypokinesia (some
patients)
- Ma proteins
antibodies
- MRI
abnormalities:
limbic
encephalitis,
variable
involvement of
hypothalamus,
basal ganglia, or
upper brainstem
Treat underlying
tumor
Kelch-like
protein 11
antibodies
- Brainstem
encephalitis<br>-
Seminomas, germ cell
tumors, teratomas
- Kelch-like
protein 11
antibodies
- MRI
abnormalities:
brainstem
encephalitis
Treat underlying
tumor
Amphiphysin
antibodies
- Usually associated
with paraneoplastic
stiff-person
syndrome<br>- Can
occur with
paraneoplastic
encephalomyelitis or
isolated myelitis (in
some patients)
- Amphiphysin
antibodies - -
Treat underlying
tumor (mainly for
paraneoplastic
stiff-person
syndrome)
The detailed table provides information on associated tumors, specific antibodies, clinical features, laboratory findings,
radiological findings, and treatment options for Paraneoplastic Encephalomyelitis and Focal Encephalitis with Antibodies
Against Intracellular Neuronal Proteins.