Topic of the month...Paraneoplastic syndromes

1. INDEX
 INTRODUCTION
INTRODUCTION
Although the discovery of antineuronal antibodies has facilitated the diagnosis of paraneoplastic
neurological disorders (PNDs), the recognition and treatment of these disorders remain a challenge. Some
antineuronal antibodies have a more syndrome-specific association than others, and some syndromes evoke
a paraneoplastic etiology more frequently than others. Because antineuronal antibodies may occur in cancer
patients without PND, their detection does not necessarily imply that a neurological disorder is
paraneoplastic. This review analyzes these issues and suggests a diagnostic strategy based on criteria
derived from clinical and immunological findings and the presence or absence of cancer. We provide an
update on the clinical features and treatment of classic PND of the central nervous system, with the proposal
of a general treatment strategy. In addition, we analyze the evidence of a hypothetically effective antitumor
immunity in patients with PND, which if confirmed would have implications for treatment of the cancer and
PND.

2. The term quot;paraneoplastic neurological disordersquot; (PNDs) refers to a group of syndromes mediated by
immune responses triggered by tumors that express nervous system proteins.[1] As a result of these immune
responses, discrete or multifocal areas of the nervous system degenerate, causing diverse symptoms and
deficits. These immune responses are often associated with specific antineuronal antibodies that can be used
as diagnostic markers of the PND and underlying cancer. Not all paraneoplastic antibodies have the same
clinical significance. Some antibodies may associate with one or a limited number of neurological syndromes
or histological types of cancer, while others are less specific or may occur without neurological symptoms.
There are PNDs with cerebrospinal fluid (CSF) and pathological evidence of being associated with
inflammatory, likely immune-mediated mechanisms but no specific antibodies or target antigens have been
identified. Beside these disparities, most paraneoplastic immune responses have in common the property of
being triggered at early stages of cancer, when the tumor or metastases are limited or undetectable by
conventional diagnostic techniques. This, along with the detection of cytotoxic T-cell responses to
onconeuronal antigens, has suggested that the small tumor burden in PND patients is largely due to an
effective anticancer immunity. If correct, the use of immunosuppressants would favor tumor growth, which
is not supported by clinical data. These findings and dilemmas are assessed in this review. Because the main
advance in the management of PND has resulted from refined clinical and immunological diagnostic criteria
and improved diagnostic tests, a major focus of this review is an update of these criteria, with the proposal
of a treatment strategy.
 General Diagnostic Approach
 Recognizing Paraneoplastic Neurological Syndromes
PNDs may affect any part of the central or peripheral nervous system, including the retina and muscle.
Some PNDs are more characteristic than others and can be considered quot;classicquot; syndromes, because they
usually associate with cancer or the clinical features readily evoke a paraneoplastic origin ( Table 1 ).[2]
Other disorders (quot;nonclassicquot;) are less characteristic and occur more frequently without cancer association,
requiring a more extensive differential diagnosis than the classic syndromes.[3]
Table 1. Paraneoplastic Syndromes of the Nervous System
Because PNDs are uncommon conditions, significant diagnostic delays are frequent even for the classic
syndromes. In a series of 50 patients with Lambert-Eaton myasthenic syndrome (LEMS), about half of the
patients were initially misdiagnosed, usually with myasthenia gravis.[4] Another study noted an inverse
correlation between the severity of the neurological symptoms and the diagnosis of the PND.[5]

3. There are several clinical features common to most PND that suggest a paraneoplastic origin. Symptoms
usually develop rapidly in days or a few weeks and then stabilize, leaving the patient severely disabled.
Exceptions do occur, and some patients develop insidious forms of PND that can be misdiagnosed as chronic
degenerative disorders.[6] Spontaneous neurological improvement, although reported in some syndromes,
[7,8] is rare and should lead to the consideration of a nonparaneoplastic etiology.
CSF studies are important to rule out disorders that may mimic PND, mainly infectious or neoplastic
meningitis. Findings consistent with PND include mild pleocytosis, elevated proteins, intrathecal synthesis of
immunoglobulins, sometimes with oligoclonal bands. However, similar CSF abnormalities can be
encountered in any inflammatory or immune-mediated disorders of the CNS, and some patients with PND
may have normal CSF studies.
Although it has been suggested that brain magnetic resonance imaging (MRI) has limited diagnostic utility
in the early stages of PND, recent reports indicate otherwise and support the importance of new MRI
technology in the diagnosis of these disorders.[9,10] One study reported brain T2-weighted abnormalities in
71% of the patients with paraneoplastic limbic encephalitis and small-cell lung cancer (SCLC).[11] Another
series of 24 patients with paraneoplastic limbic encephalitis demonstrated that all patients had fluid-
attenuated inversion recovery (FLAIR) MRI abnormalities involving one or both temporal lobes.[12] In a
series of 29 patients with anti-Ma2-associated encephalitis, brain MRI abnormalities were present in 71%;
some of these patients had abnormalities that appeared as nodular enhancing lesions, suggesting tumor
metastasis.[13] All patients who underwent repeated brain MRI had new abnormalities in subsequent
studies, including patients whose initial MRI was normal (Dalmau et al, unpublished). There is also
increasing evidence that brain [F18] fluorodeoxyglucose-positron emission tomography (FDG-PET) has
diagnostic utility in PND.[14] In the early stages of PND, FDG-PET may show hypermetabolism in the
abnormal brain regions identified by MRI, but in some patients the MRI is normal.[9]
Brain biopsy is rarely required for the diagnosis of PND. Biopsy of an abnormal area identified by MRI or
FDG-PET may be considered if a neoplastic process is suspected or if the clinical, CSF, and MRI findings
are unusual. Abnormalities supporting but not specificof PND include infiltrates of mononuclear cells,
neuronophagic nodules, neuronal degeneration, microglial proliferation, and gliosis.[15]
 Searching for Antineuronal Antibodies
Patients suspected to have a PND should be examined for antineuronal antibodies in their serum and CSF.
These antibodies preferentially associate with restricted histological types of tumors ( Table 2 ). Therefore,
in addition to supporting the diagnosis of PND, the presence of antineuronal antibodies focuses the search of
the cancer to specific organs. Well-characterized antineuronal antibodies are those directed against antigens
whose molecular identity is known or have been identified by several investigators. Partially characterized
antibodies are those whose target antigens are unknown or require further analysis in groups of individuals
serving as controls.[16-20]
Table 2. Antibodies, Paraneoplastic Syndromes, and Associated Cancers

4. There are antibodies that associate with specific disorders but do not differentiate between paraneoplastic
and nonparaneoplastic cases.[21-23] Although some of these disorders (i.e., LEMS, myasthenia gravis) can
be diagnosed on clinical and electrophysiological grounds, analysis for specific antibodies is useful in several
settings. For example, the recognition of overlapping syndromes, such as LEMS and paraneoplastic
cerebellar degeneration (PCD), is improved by antibody analysis.[24] For other syndromes such as
dysautonomia, the detection of antibodies to the neuronal acetylcholine receptor identifies a subset of
patients that benefit from immunosuppression.[23] In generalized myasthenia gravis, antibodies to the
acetylcholine receptor at the neuromuscular junction are detected in 80 to 90% of the patients with or
without thymoma.[25] A subset of patients without these antibodies harbor antibodies to muscle specific
kinase (MuSK).[26] These patients do not have thymoma and preferentially develop cranial and bulbar
weakness with a higher frequency of respiratory crisis. Detection of MuSK antibodies associates with poor
response to anticholinesterase treatments but good response to plasma exchange and cyclosporine.[27]
Different immune responses may associate with a similar neurological disorder suggesting clinical-
immunological heterogeneity ( Table 2 ). For example, antibodies to glutamic acid decarboxylase (GAD),
amphiphysin, or gephyrin have all been reported in association with the stiff-man syndrome, but the
majority of patients with antibodies to GAD do not have cancer.[28-30] Furthermore, several antineuronal
antibodies may co-occur in the same patient, particularly if the underlying tumor is SCLC. A recent study
identified concurrent Hu, CRMP5, and Zic4 antibodies in the serum or CSF of 27% of the patients with
SCLC and paraneoplastic encephalomyelitis (PEM).[31]
The serum of cancer patients without PND may contain antineuronal antibodies.[32] Usually the antibody
titers are lower than those in patients with PND, but they can overlap. In a recent report, antibodies to Hu,
CRMP5, and Zic4 were encountered in 19, 9, and 16% of SCLC patients without PND, respectively.[31] A
practical implication is that the detection of any of these antibodies in a patient with neurological symptoms

5. of unknown cause suggests a PND and predicts an underlying cancer, usually SCLC. However, detection of
these antibodies does not preclude ruling out other complications of cancer, particularly if the syndrome is
not a classic PND.
 Searching for an Occult Cancer
The discovery of an occult neoplasm in association with a particular neurological syndrome remains the
gold standard of diagnosing PND. In addition to the clinical history, evaluation of risk factors for cancer,
and serological cancer markers, most patients will need chest and abdomen computed tomography (CT) as
part of the initial evaluation or restaging of cancer. The need for other tests will vary with the patient's
gender and type of syndrome or antineuronal antibody; these may include pelvic or vaginal ultrasound,
mammograms, or testicular ultrasound. Recent studies have demonstrated that total-body FDG-PET is
useful in identifying tumors not visible with other studies.[14,33] Despite the sensitivity of FDG-PET scan,
there are instances where antineuronal antibodies can lead to the discovery of neoplasms that escape PET
detection.[34] The presence of a second cancer should be suspected if the tumor identified is different from
the cancer that usually associates with a specific syndrome or antineuronal antibody or does not express the
neuronal antigen.[5]
Patients with classic PND or with nonclassic PND but positive antineuronal antibodies, whose tumor is not
found, need close cancer surveillance. A common practice is to repeat evaluations every 6 months (i.e., body
CT or FDG-PET). The cancer usually manifests within the first 4 years of the PND, but there are rare
instances where the expected type of tumor was demonstrated 10 years later.[35]
 Patients With Cancer who Develop Neurological Symptoms
In patients with cancer the suspicion of a PND is usually based on the type of neurological syndrome (i.e.,
classic PND) and absence of other etiologies including metastasis to the nervous system, vascular and
infectious disorders, metabolic abnormalities, malnutrition, and side effects of cancer treatment.[3] Patients
in cancer remission who develop a PND should be examined for tumor recurrence. If a specific antineuronal
antibody is identified, the clinical significance varies according to the type of antibody and neurological
disorder (see diagnostic criteria, below).
 Diagnostic Criteria of PND
Because antineuronal antibodies are not always present in patients with PND and the presence of these
antibodies can occur in cancer patients without PND, a set of criteria was recently proposed by a group of
investigators.[36] These criteria take into account: (1) the type of neurological syndrome ( Table 1 ); (2) the
type of anti-neuronal antibody ( Table 2 ); and the presence or absence of cancer. Based on this information
two levels of evidence have been proposed: definite PND or possible PND ( Table 3 ).
Table 3. Diagnostic Criteria of PND of the CNS

6.  Classic Paraneoplastic Neurological Disorders of the Central Nervous System
 Paraneoplastic Cerebellar Degeneration
PCD manifests as a pancerebellar, usually symmetrical syndrome that evolves rapidly in several days or
weeks. At the early stages of PCD, the brain MRI is normal, or may rarely show cerebellar cortical
enhancement with gadolinium; as the disease progresses, cerebellar atrophy develops.[3] PCD may occur in
isolation or in association with symptoms of more widespread involvement of the CNS (encephalomyelitis).
The association of a subacute cerebellar ataxia with LEMS is highly suggestive of a paraneoplastic origin of
both disorders.
Paraneoplastic cerebellar degeneration usually precedes the diagnosis of the tumor. In these patients the
differential diagnosis should include any of the disorders shown in Table 4 . In patients with known cancer,
the differential diagnosis includes all the previously indicated neurological complications of cancer,
specifically including the cerebellar toxicity of 5-fluoruracil and cytosine arabinoside.[37,38] Thiamine
deficiency resulting in Wernicke's encephalopathy and ataxia has been reported in patients with leukemia
or lymphoma.[39]
Table 4. Differential Diagnosis of Some Classic PND
Almost all well-characterized antineuronal antibodies have been reported in association with paraneoplastic
ataxia ( Table 2 ). Serological markers that identify patients with quot;purequot; PCD include Yo,[40] Tr,[41]
voltage-gated calcium channel (VGCC), and Zic antibodies.[31,42] Patients with VGCC antibodies should
be examined for LEMS. However, despite the detection of these antibodies some patients do not develop
LEMS.[24] Between 30 and 40% of patients with PCD do not harbor antineuronal antibodies, and the
diagnosis relies on the exclusion of other etiologies and demonstration of the cancer.
 Paraneoplastic Limbic Encephalitis
Patients with paraneoplastic limbic encephalitis may present with anxiety, depression, confusion, delirium,

7. hallucinations, seizures, short-term memory loss, and dementia. MRI usually shows abnormalities in the
medial temporal lobes in T2 or FLAIR sequences. Some of these abnormalities may be hypermetabolic in
FDG-PET studies.[10] The electroencephalogram (EEG) often demonstrates uni- or bilateral temporal lobe
epileptic discharges or slow background activity.[8] The combination of clinical, MRI, EEG, and CSF
findings along with antineuronal antibody testing identifies most cases of paraneoplastic limbic encephalitis.
The antibodies more frequently associated with this disorder include anti-Hu,[11] anti-Ma2,[43] anti-
CRMP5,[44] and rarely anti-voltage-gated potassium channel antibodies.[22] The latter occur more
frequently in patients without cancer;[22] this disorder responds better to immunotherapy than other types
of limbic encephalitis.[22] About 40% of patients with paraneoplastic limbic encephalitis are seronegative or
have uncharacterized antibodies.[8,20]
Viral encephalitis should particularly be considered in the differential diagnosis of paraneoplastic limbic
encephalitis ( Table 4 ). Herpes simplex encephalitis usually results in hemorrhagic necrosis of the medial
aspect of the temporal and orbital frontal lobes. Human herpesvirus 6 encephalitis typically affects bone
marrow transplant recipients; the clinical and MRI features of this disorder can mimic to perfection
paraneoplastic limbic encephalitis.[45] Polymerase chain reaction analysis of the CSF usually establishes the
diagnosis of these viral disorders.
 Paraneoplastic Encephalomyelitis
Patients with paraneoplastic encephalomyelitis (PEM) disorder develop symptoms of multifocal
involvement of the CNS, including limbic system, cerebellum, brain stem, and spinal cord. Frequent
accompanying sensory and autonomic deficits result from involvement of the dorsal root ganglia and
sympathetic or parasympathetic peripheral nerves and ganglia.
Symptoms resulting from limbic or cerebellar encephalitis are similar to those described for the isolated
forms of these disorders. Paraneoplastic brain stem encephalitis rarely occurs in isolation.[46] The
pathological findings predominate in the lower brain stem, usually medulla and inferior olivary nuclei.[47]
In the spinal cord the inflammatory process can result in lower motor neuron dysfunction or a mixed
syndrome in which the corticospinal tracts are also involved. Because most patients have additional
neurological symptoms (i.e., sensory deficits, ataxia), the differential diagnosis with motor neuron disease is
rarely an issue.[47]
Autonomic dysfunction includes gastrointestinal paresis and pseudo-obstruction, orthostatic hypotension,
cardiac arrhythmias, erectile dysfunction, hyperhidrosis, urinary retention, and abnormal pupillary
reflexes. Paraneoplastic dysautonomia rarely occurs in isolation; it usually accompanies PEM or LEMS.[47]
Antibodies to the ganglionic acetylcholine receptors have been reported in some patients with cancer as well
as in idiopathic pandysautonomia.[23]
The antineuronal antibodies more frequently encountered in PEM are anti-Hu, anti-CRMP5, anti-Zic, and
less frequently anti-amphiphysin.[31,48,49] All of these antibodies associate with SCLC and may co-occur in
the same patient. Anti-Ma2 encephalitis predominantly affects the limbic system, hypothalamus, and upper
brain stem; the tumors more frequently involved are testicular germ-cell neoplasms and non-SCLC.[50]
 Paraneoplastic Sensory Neuronopathy
Patients with paraneoplastic sensory neuronopathy develop pain, numbness, and sensory deficits that can
affect limbs, trunk, and cranial nerves, including hearing loss. The diagnosis of radiculopathy or
multineuropathy is often first considered because the sensory deficits can be asymmetric and non-length-
dependent.[51] In addition to the sensory loss, the resulting syndrome includes sensory ataxia and decreased
or absent reflexes. Nerve conduction studies show decreased or absent sensory nerve action potentials with
normal or near-normal motor conduction velocities.[52] Paraneoplastic sensory neuronopathy may occur in

8. isolation, but often precedes or coincides with the development of PEM, suggesting a common pathogenic
mechanism. In both instances, detection of anti-Hu antibodies is frequent.[53] Sensorimotor neuropathies
associated with anti-Hu antibodies often result from mixed involvement of dorsal root ganglia and
peripheral nerves. In the latter, serum anti-CRMP5 antibodies can also be present.[48,49]
Up to 18% of patients with paraneoplastic sensory neuronopathy do not have serum antineuronal
antibodies.[53] The differential diagnosis is shown in Table 4 ; in cancer patients it includes chemotherapy-
induced neuropathy (cisplatin, paclitaxel, docetaxel, vincristine). In patients without cancer, Sjögren's
syndrome should be considered; some patients with this syndrome can develop dorsal root ganglia
dysfunction along with myelopathy and encephalopathy, mimicking PEM.[54]
 Paraneoplastic Opsoclonus-Myoclonus
Opsoclonus is an eye movement disorder characterized by chaotic, conjugate, arrhythmic, and
multidirectional saccades. These symptoms often associate with myoclonus and truncal ataxia. The tumors
more frequently involved are SCLC, breast and gynecological cancers in adults, and neuroblastoma in
children. The majority of patients do not harbor antineuronal antibodies. Detection of anti-Ri antibodies
usually indicate the presence of breast or gynecological cancers, or less frequently SCLC.[55] Other
antineuronal antibodies that may occur in a minority of patients include Hu,[56] CRMP5/CV2,[48] Zic2,[57]
amphiphysin,[49] Yo,[40] and Ma2 antibodies.[13] Paraneoplastic opsoclonus may respond to treatment,
but improvement depends on tumor control.[7]
There is an idiopathic form of opsoclonus-myoclonus for which there are no serological markers. Two
patients with this disorder had antibodies to the adenomatous polyposis coli protein (APC).[57] Compared
with paraneoplastic opsoclonus, patients with idiopathic opsoclonus are younger and the disorder responds
better to immunotherapy.[7]
The differential diagnosis of opsoclonus is extensive, particularly if a paraneoplastic origin is suspected but
the presence of a tumor is not known ( Table 4 ).
 Treatment and Outcome of Paraneoplastic Neurological Disorders
Studies have emphasized the importance of early cancer treatment to achieve the stabilization or
improvement of the PND.[58] Chalk and colleagues demonstrated improvement of the neuromuscular
transmission in 10 of 11 patients with LEMS after treating the tumor.[59] In a study of paraneoplastic
opsoclonus, all patients who received oncological treatment showed complete or partial neurological
improvement, while those whose cancer was not treated showed neurological deterioration, regardless of
immunotherapy.[7]
For other PND of the CNS, the neurological response to oncological treatment is less satisfactory.
Improvement or stabilization of anti-Hu-associated PEM was observed in 37% of patients who received
antineoplastic therapy.[5] Patients with pure sensory neuronopathy were more likely to improve than those
with PEM. The neurological response to oncological treatment was worse in a series of patients with anti-
Yo-associated PCD in which none of 25 patients with this disorder improved after cancer therapy.
Furthermore, 37% of these patients developed PCD while undergoing cancer therapy or during tumor
remission.[60]
In contrast, patients with anti-Ma2 encephalitis may show dramatic improvement of neurological symptoms
after cancer treatment or immunotherapy. In a series of 18 patients with anti-Ma2 encephalitis, seven
patients had complete or partial remission of neurological symptoms, usually in association with complete
tumor response to therapy.[13] A more recent series of 38 patients with anti-Ma2 encephalitis showed that
33% had neurological improvement, three with complete recovery; 21% had long-term stabilization
(median follow-up 3½; years); and 46% deteriorated. Features associated with improvement or stabilization
included male gender, underlying testicular germ-cell tumors with complete response to treatment, and

9. limited involvement of the nervous system (Dalmau, unpublished data). The reasons for the better outcome
of patients with anti-Ma2 encephalitis are unclear. However, this disorder frequently associates with
testicular germ-cell tumors, which in contrast to other cancers can be completely removed and are very
responsive to oncological treatments.
Although PND of the CNS usually do not respond to immunotherapy alone, there are several case reports of
patients who stabilized or improved after immunosuppression or immunomodulatory treatments, such as
plasma exchange or intravenous immunoglobulins (IVIg).[58,61] The main disorders that may show
response to immunotherapy or corticosteroids are opsoclonus-myoclonus and limbic encephalitis.[7,22] A
recent series of selected patients (Rankin disability score between 2 and 4) with diverse PND showed that in
patients without a known tumor, immunotherapy (plasma exchange and oral cyclophosphamide) at the
early stages of the PND may result in improvement; patients with multifocal encephalomyelitis were not
included.[62]
Figure 1. Recommended approach to treatment of PND of the CNS. AMay include IVIg and/or intravenous
or oral steroids and/or plasma exchange. BMay include cyclophosphamide and/or rituximab, or tacrolimus.
Variable efficacy (class 4 to 5 level of evidence) has been reported for IVIg, steroids, plasma exchange, or
protein-A immunoglobulin G absorption, cyclophosphamide, and rituximab.[58,75-77] Tacrolimus has been
suggested as treatment;[78] clinical studies are not available. *Because patients with limbic encephalitis or
opsoclonus/myoclonus may show dramatic improvement to immunosuppression, patients with these two
disorders and KPS < 50 may be considered for immunosuppression. KPS, Karnofsky performance status.
 Assessment of the Clinical Efficacy of Antitumor Immunity
It has been suggested that paraneoplastic immunity is clinically effective in controlling tumor growth,
accounting for the small size and limited metastatic burden of tumors associated with PND. However, there

10. are only two clinical series, both in patients with SCLC, supporting this hypothesis. One study was
conducted in patients without PND and showed that those with low titers of anti-Hu antibodies were more
likely to have limited tumor stage and better response to chemotherapy than patients without antibodies.
[63] In this study the strongest association was between the presence of anti-Hu antibodies and increased
response to chemotherapy; the mechanisms underlying the chemosensitivity were not examined. The second
study compared SCLC patients with and without LEMS and found that patients with LEMS had longer
survival. Because 14 of the 15 LEMS patients developed the neurological disorder before the tumor
diagnosis, a lead-time bias could not be ruled out.
In addition to these two series, other data supporting clinically effective antitumor immunity derives from a
small number of patients with spontaneous tumor regression.[64-67] However, the evidence for the tumor
regression is often unclear. Some of the reported patients received oncological treatment and therefore the
tumor regression was not spontaneous;[66] others lacked pathological demonstration of a tumor;[65,66] and
others did not have detectable immune responses.[67]
Despite experimental evidence that some patients with PCD develop cytotoxic T-cell responses against the
paraneoplastic antigen (Yo or CDR2) expressed by the tumor,[68] all series of patients with anti-Yo-
associated PCD raise doubt on the efficacy of the antitumor immune response.[40,60] For example, in a
series of 19 patients with PCD, the neurological disorder preceded or coincided with the diagnosis of the
cancer in 15 patients, and in seven the paraneoplastic antibodies led to exploratory laparotomy. Despite this,
72% of all patients had stage III ovarian cancer.[69] In another series, 34 of 55 patients with anti-Yo-
associated PCD developed neurological symptoms that led to the search for cancer, usually ovarian or
breast cancer.[40] Regardless of this lead-time bias, seven patients had widely metastatic cancer and 26
regional metastases, a figure closely similar to that encountered in patients without PND. In another series
of 34 patients with anti-Yo-associated PCD, all 12 patients with breast cancer and 15 of 18 patients with
gynecological cancers had metastatic lymph nodes at the time of tumor diagnosis.[60] The median survival
was 100 months for patients with breast cancer and 22 for those with gynecological cancer.
All large series of patients with PND of the CNS suggest a lead-time bias of early tumor diagnosis as a result
of increased surveillance.[5,35,47,60,69-71] In each of these studies most patients developed PND before the
tumor diagnosis, and none of the patients had spontaneous tumor regression. Furthermore, recent FDG-
PET studies in SCLC patients without PND show that ~60% have limited disease at the time of tumor
diagnosis.[72] These studies suggest that with better diagnostic techniques the tumor staging of patients
without PND is becoming similar to that of patients with PND in whom the neurological disorder or
detection of antibodies prompt the search for cancer. Furthermore, in two series of patients with PND the
use of immunotherapy did not favor tumor growth as one would expect if the antitumor immune response
was clinically effective.[62,73]
Overall, rather than an effective antitumor immunity, most clinical series of PND suggest that the immune
response is triggered at early stages of cancer development and that the neurological symptoms forewarn of
the presence of a tumor that otherwise would have clinically manifested months or years later. For example,
carcinoma in situ of the testis (also known as intratubular germ-cell tumor) takes ~5 years to become
invasive, and therefore detectable.[74] We reported two patients whose PND led to the diagnosis of
carcinoma in situ of the testis at the preinvasive stage.[13]
 General Treatment Strategy for PND of the CNS
In summary, data from the above studies suggest: (1) the diagnosis and treatment of the tumor is the main
factor associated with stabilization or improvement of PND and should be the main goal in the management
of these disorders; (2) there is no evidence that immunosuppression favors tumor growth in PND patients;
and (3) some patients benefit from immunosuppression.
In view of these conclusions, a general treatment strategy for PND of the CNS is proposed (Fig. 1).[75-78]
Because the simultaneous use of chemotherapy and some immunosuppressants may result in significant

11. toxicity, two levels of immunological intervention are suggested. Patients with progressive PND who are
receiving chemotherapy should be considered for immunosuppression or immunomodulation that may
include oral or intravenous corticosteroids, IVIg, or plasma exchange. Patients with progressive PND who
are not receiving chemotherapy should be considered for more aggressive immunosuppression that may
include oral or intravenous cyclophosphamide, tacrolimus, cyclosporine, or rituximab. Although there is no
compelling evidence than any of these immunosuppressants is better than others for patients with PND, the
authors favor the use of corticosteroids, IVIg, and cyclophosphamide. Clinical trials with homogeneous
groups of PND patients (same antibody, same syndrome) assessing the proposed treatment design and
immunosuppressants should be the focus of future studies.
References
1. Dalmau JO, Posner JB. Paraneoplastic syndromes affecting the nervous system. Semin Oncol
1997;24:318-328
2. Rudnicki SA, Dalmau J. Paraneoplastic syndromes of the spinal cord, nerve, and muscle. Muscle
Nerve 2000;23:1800-
3. Posner JB. Neurologic Complications of Cancer. Philadelphia F.A. Davis Company; 1995
4. O'Neill JH, Murray NM, Newsom-Davis J. The Lambert-Eaton myasthenic syndrome. A review of 50
cases. Brain 1988;111:577-596
5. Graus F, Keime-Guibert F, Rene R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis:
analysis of 200 patients. Brain 2001;124:1138-1148
6. Graus F, Bonaventura I, Uchuya M, et al. Indolent anti-Hu-associated paraneoplastic sensory
neuropathy. Neurology 1994;44:2258-2261
7. Bataller L, Graus F, Saiz A, Vilchez JJ. Clinical outcome in adult onset idiopathic or paraneoplastic
opsoclonus-myoclonus. Brain 2001;124:437-443
8. Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB, Dalmau J. Paraneoplastic limbic
encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients.
Brain 2000;123:1481-1494
9. Dadparvar S, Anderson GS, Bhargava P, et al. Paraneoplastic encephalitis associated with cystic
teratoma is detected by fluorodeoxyglucose positron emission tomography with negative magnetic
resonance image findings. Clin Nucl Med 2003;28:893-896
10. Fakhoury T, Abou-Khalil B, Kessler RM. Limbic encephalitis and hyperactive foci on PET scan.
Seizure 1999;8:427-431
11. Alamowitch S, Graus F, Uchuya M, Rene R, Bescansa E, Delattre JY. Limbic encephalitis and small
cell lung cancer. Clinical and immunological features. Brain 1997;120:923-928
12. Lawn ND, Westmoreland BF, Kiely MJ, Lennon VA, Vernino S. Clinical, magnetic resonance
imaging, and electroencephalographic findings in paraneoplastic limbic encephalitis. Mayo Clin Proc
2003;78:1363-1368
13. Rosenfeld MR, Eichen JG, Wade DF, Posner JB, Dalmau J. Molecular and clinical diversity in

12. paraneoplastic immunity to Ma proteins. Ann Neurol 2001;50:339-348
14. Crotty E, Patz EF Jr. FDG-PET imaging in patients with paraneoplastic syndromes and suspected
small cell lung cancer. J Thorac Imaging 2001;16:89-93
15. Henson RA, Urich H. Cancer and the Nervous System: The Neurologic Manifestations of Systemic
Malignant Disease. London: Blackwell Scientific; 1982
16. Bataller L, Wade DF, Graus F, Rosenfeld MR, Dalmau J. The MAZ protein is an autoantigen of
Hodgkin's disease and paraneoplastic cerebellar dysfunction. Ann Neurol 2003;53: 123-127
17. Chan KH, Vernino S, Lennon VA. ANNA-3 anti-neuronal nuclear antibody: marker of lung cancer-
related autoimmunity. Ann Neurol 2001;50:301-311
18. Vernino S, Lennon VA. New Purkinje cell antibody (PCA-2): marker of lung cancer-related
neurological autoimmunity. Ann Neurol 2000;47:297-305
19. Sillevis SP, Kinoshita A, de Leeuw B, et al. Paraneoplastic cerebellar ataxia due to autoantibodies
against a glutamate receptor. N Engl J Med 2000;342:21-27
20. Scheid R, Honnorat J, Delmont E, Urbach H, Biniek R. A new anti-neuronal antibody in a case of
paraneoplastic limbic encephalitis associated with breast cancer. J Neurol Neurosurg Psychiatry
2004;75:338-340
21. Motomura M, Johnston I, Lang B, Vincent A, Newsom-Davis J. An improved diagnostic assay for
Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry 1995; 58:85-87
22. Pozo-Rosich P, Clover L, Saiz A, Vincent A, Graus F. Voltage-gated potassium channel antibodies in
limbic encephalitis. Ann Neurol 2003;54:530-533
23. Vernino S, Low PA, Fealey RD, Stewart JD, Farrugia G, Lennon VA. Autoantibodies to ganglionic
acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med 2000;343:847-855
24. Mason WP, Graus F, Lang B, et al. Small-cell lung cancer, paraneoplastic cerebellar degeneration and
the Lambert-Eaton myasthenic syndrome. Brain 1997;120:1279-1300
25. Vincent A, Newsom-Davis J. Acetylcholine receptor antibody as a diagnostic test for myasthenia
gravis: results in 153 validated cases and 2967 diagnostic assays. J Neurol Neurosurg Psychiatry
1985;48:1246-1252
26. Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A. Auto-antibodies to the
receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor
antibodies. Nat Med 2001;7:365-368
27. Evoli A, Tonali PA, Padua L, et al. Clinical correlates with anti-MuSK antibodies in generalized
seronegative myasthenia gravis. Brain 2003;126:2304-2311
28. Solimena M, Folli F, Aparisi R, Pozza G, De Camilli P. Autoantibodies to GABA-ergic neurons and
pancreatic beta cells in stiff-man syndrome. N Engl J Med 1990;322:1555-1560
29. Butler MH, Hayashi A, Ohkoshi N, et al. Autoimmunity to gephyrin in Stiff-Man syndrome. Neuron
2000;26:307-312

13. 30. Folli F, Solimena M, Cofiell R, et al. Autoantibodies to a 128-kd synaptic protein in three women with
the stiff-man syndrome and breast cancer. N Engl J Med 1993;328:546-551
31. Bataller L, Wade D, Graus F, Stacey BS, Rosenfeld MR, Dalmau J. Antibodies to Zic4 in
paraneoplastic neurologic disorders and small-cell lung cancer. Neurology 2004;62:778-782
32. Drlicek M, Bianchi G, Bogliun G, et al. Antibodies of the anti-Yo and anti-Ri type in the absence of
paraneoplastic neurological syndromes: a long-term survey of ovarian cancer patients. J Neurol
1997;244:85-89
33. Rees JH, Hain SF, Johnson MR, et al. The role of [18F]fluoro-2-deoxyglucose-PET scanning in the
diagnosis of paraneoplastic neurological disorders. Brain 2001;124: 2223-2231
34. Debourdeau P, Gligorov J, Zammit C. A serologic marker of paraneoplastic limbic and brain-stem
encephalitis in patients with testicular cancer. N Engl J Med 1999;341:1475-1476
35. Rojas-Marcos I, Rousseau A, Keime-Guibert F, et al. Spectrum of paraneoplastic neurologic disorders
in women with breast and gynecologic cancer. Medicine (Baltimore) 2003;82:216-223
36. Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteria for paraneoplastic
neurological syndromes. J Neurol Neurosurg Psychiatry 2004;75:1135-1140
37. Koenig H, Patel A. The acute cerebellar syndrome in 5-fluorouracil chemotherapy: a manifestation of
fluoroacetate intoxication. Neurology 1970;20:416
38. Zawacki T, Friedman JH, Grace J, Shetty N. Cerebellar toxicity of cytosine arabinoside: clinical and
neuropsychological signs. Neurology 2000;55:1234
39. Engel PA, Grunnet M, Jacobs B. Wernicke-Korsakoff syndrome complicating T-cell lymphoma:
unusual or unrecognized? South Med J 1991;84:253-256
40. Peterson K, Rosenblum MK, Kotanides H, Posner JB. Paraneoplastic cerebellar degeneration. I. A
clinical analysis of 55 anti-Yo antibody-positive patients. Neurology 1992;42: 1931-1937
41. Bernal F, Shams'ili S, Rojas I, et al. Anti-Tr antibodies as markers of paraneoplastic cerebellar
degeneration and Hodgkin's disease. Neurology 2003;60:230-234
42. Graus F, Lang B, Pozo-Rosich P, Saiz A, Casamitjana R, Vincent A. P/Q type calcium-channel
antibodies in paraneoplastic cerebellar degeneration with lung cancer. Neurology 2002;59:764-766
43. 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;340:1788-1795
44. Kinirons P, Fulton A, Keoghan M, Brennan P, Farrell MA, Moroney JT. Paraneoplastic limbic
encephalitis (PLE) and chorea associated with CRMP-5 neuronal antibody. Neurology 2003;61:1623-
1624
45. Wainwright MS, Martin PL, Morse RP, et al. Human herpesvirus 6 limbic encephalitis after stem cell
transplantation. Ann Neurol 2001;50:612-619
46. Baloh RW, DeRossett SE, Cloughesy TF, et al. Novel brainstem syndrome associated with prostate
carcinoma. Neurology 1993;43:2591-2596

14. 47. Dalmau J, Graus F, Rosenblum MK, Posner JB. Anti-Hu-associated paraneoplastic
encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine (Baltimore)
1992;71:59-72
48. Yu Z, Kryzer TJ, Griesmann GE, Kim K, Benarroch EE, Lennon VA. CRMP-5 neuronal
autoantibody: marker of lung cancer and thymoma-related autoimmunity. Ann Neurol 2001;49:146-
154
49. Saiz A, Dalmau J, Butler MH, et al. Anti-amphiphysin I antibodies in patients with paraneoplastic
neurological disorders associated with small cell lung carcinoma. J Neurol Neurosurg Psychiatry
1999;66:214-217
50. Dalmau J, Gultekin SH, Voltz R, et al. Ma1, a novel neuron- and testis-specific protein, is recognized
by the serum of patients with paraneoplastic neurological disorders. Brain 1999;122:27-39
51. Horwich MS, Cho L, Porro RS, Posner JB. Subacute sensory neuropathy: a remote effect of
carcinoma. Ann Neurol 1977; 2:7-19
52. Camdessanche JP, Antoine JC, Honnorat J, et al. Paraneoplastic peripheral neuropathy associated
with anti-Hu antibodies. A clinical and electrophysiological study of 20 patients. Brain 2002;125:166-
175
53. Molinuevo JL, Graus F, Serrano C, Rene R, Guerrero A, Illa I. Utility of anti-Hu antibodies in the
diagnosis of paraneoplastic sensory neuropathy. Ann Neurol 1998;44: 976-980
54. de Seze J, Stojkovic T, Hachulla E, et al. Myelopathy-Sjogren's syndrome association: analysis of
clinical and radiological findings and clinical course. Rev Neurol (Paris) 2001;157:669-678
55. Luque FA, Furneaux HM, Ferziger R, et al. Anti-Ri: an antibody associated with paraneoplastic
opsoclonus and breast cancer. Ann Neurol 1991;29:241-251
56. Hersh B, Dalmau J, Dangond F, Gultekin S, Geller E, Wen PY. Paraneoplastic opsoclonus-myoclonus
associated with anti-Hu antibody. Neurology 1994;44:1754-1755
57. Bataller L, Rosenfeld MR, Graus F, Vilchez JJ, Cheung NK, Dalmau J. Autoantigen diversity in the
opsoclonus-myoclonus syndrome. Ann Neurol 2003;53:347-353
58. Rosenfeld MR, Dalmau J. Current therapies for paraneoplastic neurologic syndromes. Curr Treat
Options Neurol 2003; 5:69-77
59. Chalk CH, Murray NM, Newsom-Davis J, O'Neill JH, Spiro SG. Response of the Lambert-Eaton
myasthenic syndrome to treatment of associated small-cell lung carcinoma. Neurology 1990;40:1552-
1556
60. Rojas I, Graus F, Keime-Guibert F, et al. Long-term clinical outcome of paraneoplastic cerebellar
degeneration and anti-Yo antibodies. Neurology 2000;55:713-715
61. David YB, Warner E, Levitan M, Sutton DM, Malkin MG, Dalmau JO. Autoimmune paraneoplastic
cerebellar degeneration in ovarian carcinoma patients treated with plasma-pheresis and
immunoglobulin. A case report. Cancer 1996;78: 2153-2156
62. Vernino S, O'Neill BP, Marks RS, O'Fallon JR, Kimmel DW. Immunomodulatory treatment trial for
paraneoplastic neurological disorders. Neurooncol 2004;6:55-62

15. 63. Graus F, Dalmou J, Rene R, et al. Anti-Hu antibodies in patients with small-cell lung cancer:
association with complete response to therapy and improved survival. J Clin Oncol 1997; 15:2866-
2872
64. Gill S, Murray N, Dalmau J, Thiessen B. Paraneoplastic sensory neuronopathy and spontaneous
regression of small cell lung cancer. Can J Neurol Sci 2003;30:269-271
65. Byrne T, Mason WP, Posner JB, Dalmau J. Spontaneous neurological improvement in anti-Hu
associated encephalomyelitis. J Neurol Neurosurg Psychiatry 1997;62:276-278
66. Darnell RB, DeAngelis LM. Regression of small-cell lung carcinoma in patients with paraneoplastic
neuronal antibodies. Lancet 1993;341:21-22
67. Zaheer W, Friedland ML, Cooper EB, et al. Spontaneous regression of small cell carcinoma of lung
associated with severe neuropathy. Cancer Invest 1993;11:306-309
68. Albert ML, Darnell JC, Bender A, Francisco LM, Bhardwaj N, Darnell RB. Tumor-specific killer cells
in paraneoplastic cerebellar degeneration. Nat Med 1998;4:1321-1324
69. Hetzel DJ, Stanhope CR, O'Neill BP, Lennon VA. Gynecologic cancer in patients with subacute
cerebellar degeneration predicted by anti-Purkinje cell antibodies and limited in metastatic volume.
Mayo Clin Proc 1990;65:1558-1563
70. Sillevis SP, Grefkens J, de Leeuw B, et al. Survival and outcome in 73 anti-Hu positive patients with
paraneoplastic encephalomyelitis/sensory neuronopathy. J Neurol 2002;249: 745-753
71. Lucchinetti CF, Kimmel DW, Lennon VA. Paraneoplastic and oncologic profiles of patients
seropositive for type 1 antineuronal nuclear autoantibodies. Neurology 1998;50:652-657
72. Kamel EM, Zwahlen D, Wyss MT, Stumpe KD, von Schulthess GK, Steinert HC. Whole-body (18)F-
FDG PET improves the management of patients with small cell lung cancer. J Nucl Med
2003;44:1911-1917
73. Keime-Guibert F, Graus F, Broet P, et al. Clinical outcome of patients with anti-Hu-associated
encephalomyelitis after treatment of the tumor. Neurology 1999;53:1719-1723
74. Dieckmann KP, Skakkebaek NE. Carcinoma in situ of the testis: review of biological and clinical
features. Int J Cancer 1999;83:815-822
75. Batchelor TT, Platten M, Hochberg FH. Immunoadsorption therapy for paraneoplastic syndromes. J
Neurooncol 1998; 40:131-136
76. Keime-Guibert F, Graus F, Fleury A, et al. Treatment of paraneoplastic neurological syndromes with
antineuronal antibodies (anti-Hu, anti-Yo) with a combination of immunoglobulins,
cyclophosphamide and methylprednisolone. J Neurol Neurosurg Psychiatry 2000;68:479-482
77. Sillevis Smitt P, Gratama JW, Shamsili S, Hooijkaas H. van't Veer M. Rituximab induced depletion of
circulating B cells in anti-Hu and anti-Yo associated paraneoplastic neurologic syndromes. Neurology
2003;60(suppl 1):A3
78. Albert ML, Austin LM, Darnell RB. Detection and treatment of activated T cells in the cerebrospinal
fluid of patients with paraneoplastic cerebellar degeneration. Ann Neurol 2000;47:9-17

16. Addendum
 A new version of topic of the month publication is uploaded in my web site every month (it remains for a
month and is changed with the monthly update of the neurology bulletin
at:.http://neurology.yassermetwally.com)
 To download the current version of topic of the month publication follow the link
quot;http://neurology.yassermetwally.com/topic.zipquot;
 You can also download the current version of topic of the month publication from within the publication or
go to my web site at: quot;http://yassermetwally.comquot; to download it.
 At the end of each year, all the publications are compiled on a single CD-ROM, please author to know more
details.
 Screen resolution is better set at 1024*768 pixel screen area for optimum display
 For an archive of the previously published topics in downloadable PDF format go to
http://yassermetwally.net, then under pages in the right panel, scroll down and click on the text entry quot;topic
of the monthquot;
 In order to view a list of the previously published topics in downloadable PDF format, follow the link
http://wordpress.com/tag/neurological-topic-of-the-month/ or click on it if it appears as a link in your PDF
reader.
The author: Professor Yasser Metwally, professor of neurology, Ain Shams university, Cairo, Egypt
www.yassermetwally.com