Serological evaluation of patients who present with a subacute

neurological disorder of undetermined etiology,

especially those with known risk factors for cancer.

 

Directing a focused search for cancer

 

Investigating neurological symptoms that appear in the course of,

or after, cancer therapy, and are not explainable by metastasis

 

Differentiating autoimmune neuropathies from neurotoxic effects

of chemotherapy

 

Monitoring the immune response of seropositive patients in the

course of cancer therapy

 

Detecting early evidence of cancer recurrence in previously

seropositive patients

Paraneoplastic autoimmune neurological disorders reflect a

patient's humoral and cellular immune responses to cancer.

The cancer may be new or recurrent, is usually limited in

metastatic volume, and is often occult by standard imaging

procedures. Autoantibodies specific for onconeural

proteins found in the plasma membrane, cytoplasm, and

nucleus of neurons, glia or muscle are generated in this immune

response, and serve as serological markers of paraneoplastic

autoimmunity. Cancers recognized in this

context most commonly are small-cell lung carcinoma (SCLC),

thymoma, ovarian (or related mullerian) carcinoma, breast

carcinoma, and Hodgkin's lymphoma. Pertinent childhood

neoplasms recognized thus far include neuroblastoma, thymoma,

Hodgkin's lymphoma, and chondroblastoma. An individual patient's

autoantibody profile can predict a specific neoplasm with 90%

certainty, but not the neurological syndrome.

 

Four classes of autoantibodies are recognized in this

evaluation:

1.   Neuronal nuclear (ANNA-1, ANNA-2, ANNA-3)

2.   Anti-Glial/Neuronal Nuclear (AGNA-1; aka Sox1)

3.   Neuronal and muscle cytoplasmic (PCA-1, PCA-2, PCA-Tr,

      CRMP-5, amphiphysin, and striational)

4.   Plasma membrane cation channel, calcium channels,

      P/Q-type and N-type calcium channel, dendrotoxin-sensitive

      potassium channels and neuronal (ganglionic) and

      muscle nicotinic acetylcholine receptors

      (AChR). These autoantibodies are potential effectors

      of neurological dysfunction.

 

Seropositive patients usually present with subacute neurological

symptoms and signs such as encephalopathy,

cerebellar ataxia; myelopathy; radiculopathy; plexopathy; or sensory,

sensorimotor, or autoimmune neuropathy, with or without

a neuromuscular transmission disorder: Lambert-Eaton

syndrome (LES), myasthenia gravis (MG), or neuromuscular hyper-

excitability. Initial signs may be subtle, but a subacute multifocal and

progressive syndrome usually evolves. Sensorimotor neuropathy and

cerebellar ataxia are common presentations, but the clinical picture in

some patients is dominated by striking gastrointestinal dysmotility,

limbic encephalopathy, basal ganglionitis, or cranial neuropathy

(especially loss of vision, hearing, smell, or taste).

 

Cancer risk factors include past or family history of cancer, history of

smoking, or social or environmental exposure to carcinogens.

Early diagnosis and treatment of the neoplasm favor less neurological

morbidity and offer the best hope for survival.

 

See "Paraneoplastic Evaluation Algorithm" in Special Instructions.

NEURONAL NUCLEAR ANTIBODIES

      Antineuronal Nuclear Antibody-Type 1 (ANNA-1)

                  <1:240  

      Antineuronal Nuclear Antibody -Type 2 (ANNA-2)  

                  <1:240

      Antineuronal Nuclear Antibody -Type 3 (ANNA-3)

                  <1:240

      Anti-Glial/Neuronal Nuclear Antibody-Type 1 (AGNA-1)

                  <1:240

 

NEURONAL AND MUSCLE CYTOPLASMIC ANTIBODIES

      Purkinje Cell Cytoplasmic Antibody, Type 1 (PCA-1)

                  <1:240

      Purkinje Cell Cytoplasmic Antibody, Type 2 (PCA-2)

                  <1:240

      Purkinje Cell Cytoplasmic Antibody, Type Tr  (PCA-Tr)

                  <1:240

      Amphiphysin Antibody

                  <1:240

      CRMP-5-IgG

                  <1:240

Note:   Titers lower than 1:240 are detectable by recombinant

                CRMP-5 Western blot analysis. CRMP-5 Western blot

                analysis will be done on request on stored serum (held 4

                weeks). This supplemental testing is recommended in

                cases of chorea, vision loss, cranial neuropathy, and

                myelopathy. Call the Neuroimmunology Laboratory at

                800-533-1710 or 507-266-5700 to request CRMP-5

Western blot.

      Striational (Striated Muscle) Antibodies

                  <1:60

 

CATION CHANNEL ANTIBODIES

      N-Type Calcium Channel Antibody

                  < or = 0.03 nmol/L

      P/Q-Type Calcium Channel Antibody

                  < or = 0.02 nmol/L

      ACh Receptor (Muscle) Binding Antibody

                  < or = 0.02 nmol/L

      AChR Ganglionic Neuronal Antibody

                < or = 0.02 nmol/L

      Voltage-Gated Potassium Channel Antibody

                < or = 0.02 nmol/L

      GAD65 Antibody

                < or = 0.02 nmol/L

 

 

Neuron-restricted patterns of IgG staining that do not fulfill criteria

for amphiphysin, ANNA-1, ANNA-2, ANNA-3, PCA-1, PCA-2, PCA-Tr,

or CRMP-5-IgG may be reported as "unclassified antineuronal IgG."

Complex patterns that include non-neuronal elements may be reported

as "uninterpretable."

Antibodies directed at onconeural proteins shared by neurons,

glia, muscle, and certain cancers are valuable serological markers

of a patient's immune response to cancer. They are not found

in healthy subjects, and are usually accompanied by subacute

neurological symptoms and signs. Several autoantibodies have

a syndromic association, but no autoantibody predicts

a specific neurological syndrome. Conversely, a positive

autoantibody profile has 80% to 90% predictive value for a specific

cancer. It is not uncommon for more than 1 paraneoplastic

autoantibody to be detected, each predictive of the same cancer.

Negative results do not exclude cancer.

 

The neuronal voltage-gated potassium channel Ab assay will

not be performed for children (aged 18 years or younger)

because normal values are not yet established for the

pediatric population.

 

This evaluation does not include Ma2 autoantibody (alias: MaTa) or

the NMDA receptor (NR2B). Ma2 autoantibody has been

described in patients with brainstem and

limbic encephalitis in the context of testicular germ cell

neoplasms. Scrotal ultrasound is advisable in men who

present with unexplained subacute encephalitis.

NMDA receptor antibodies have been reported in women with

paraneoplastic encephalitis related to ovarian teratoma.

 

1.   Lennon VA, Kryzer TJ, Griesmann GE, et al:  Calcium-channel

      antibodies in the Lambert-Eaton syndrome and other paraneoplastic

      syndromes. N Engl J Med 1995 June 1;332(22):1467-1474

 

2.   Lennon VA:  Calcium channel and related paraneoplastic

      disease autoantibodies. In Textbook of Autoantibodies. Edited

      by JB Peter, Y Schoenfeld. The Netherlands, Elsevier

      Science Publishers, B.V., 1996, pp 139-147

  

3.   Pittock SJ, Lucchinetti CF, Lennon VA:  Anti-neuronal nuclear

      autoantibody-type 2: paraneoplastic accompaniments.

      Ann Neurol 2003 May;53(5):580-587

 

4.   Cross SA, Salomao DR, Parisi JE, et al:  Paraneoplastic

      autoimmune optic neuritis with retinitis defined by CRMP-5-IgG.

      Ann Neurol 2003 July;54(1):38-50

 

5.   Voltz R, Gultekin SH, Rosenfeld MR, et al:  A serologic marker of

      paraneoplastic limbic and brain-stem encephalitis in patients with

      testicular cancer. N Engl J Med 1999 June 10;340(23):1788-1795

 

6.   Vernino S, Tuite P, Adler CH, et al: Paraneoplastic chorea associated

      with CRMP-5 neuronal antibody and lung carcinoma.

      Ann Neurol 2002 May;51(1):625-630

 

7.   Pittock SJ, Kryzer TJ, Lennon VA: Paraneoplastic antibodies coexist

      and predict cancer, not neurological syndrome. Ann Neurol 2004;56(5):

      715-719

 

8.   Pittock SJ, Yoshikawa H, Ahlskog JE, et al: Glutamic acid

      decarboxylase autoimmunity with brainstem, extrapyramidal and spinal

      cord dysfunction. Mayo Clin Proc 2006;81(9):1207-1214

 

9.  Graus F, Vincent A, Pozo-Rosich P, et al:  Anti-glial nuclear

      antibody:  marker of lung cancer-related paraneoplastic neurological

      syndromes. J Neuroimmunol 2005;154(1-2):166-171

 

10. Lachance D, Kryzer TJ, Pittock SJ, et al:  Anti-neuronal nuclear

      antibody type 4 (ANNA-4), Anovel paraneoplastic marker of small-

      cell lung carcinoma (SCLC). Neurology 2006;66 (Suppl2):A340

 

11. Sabater L, Saiz A, Titulaer MG, et al: Sox 1 antibodies are markers

       of paraneoplastic Lambert-Eaton myasthenic syndrome. Neurology

       2007;68(Suppl 1):A290-A291

 

12. Dalmau J, Tuzun E, Wu H-Y, et al: Paraneoplastic anti-N-methyl-D-

       asparate receptor encephalitis associated with ovarian teratome.

       Ann Neurol 2007;61:25-36

 

13. Tan K. Lennon V, Pittock S: Voltage-gated potassium channel (VGKC)

        autoimmunity, Abstract, Annual Meeting of American Neurological

        Association, Washington DC, (October) 2007