It is well-known that lung cancer may cause central
and peripheral nervous system involvement. Apart from
metastases there may also be non-metastatic effects of
cancer on the nervous system and remote effects of cancer
are a major part of these. It has been shown that 42% of
lung cancer patients are diagnosed with cancer-related
neurological complications either at initial presentation or
at follow-up and metastatic disease (intracranial and spinal
lesions) and paraneoplastic syndromes are the most important
of these complications [
1].
METASTATIC EFFECTS OF LUNG CANCER ON NERVOUS SYSTEM
In addition to brain metastases, spinal and leptomeningeal
metastases may be seen, but these are relatively rare
(Figures 1, 2). Metastases of peripheral nervous system
have a lower incidence than central nervous system metastases.
Pancoast tumor (apical tumor of lung) metastasizing
to the brachial plexus is a well-known example.
Fig 1: MRI image of contrast-enhanced infratentorial and
posterior dural brain metastasis in a patient with non-small
cell lung cancer (The arrows show the lesions)
Fig 2: MRI image of leptomeningeal metastasis in nonsmall
cell lung cancer (The arrow shows the lesion)
NON-METASTATIC EFFECTS OF LUNG CANCER ON THE CENTRAL AND PERIPHERAL NERVOUS SYSTEM
These may involve mainly vascular disorders such as
hypocoagulability resulting in hemorrhage or hypercoagulability
(infarction), side effects of therapy such as surgery,
irradiation, chemotherapy and remote effects on brain and
cranial nerves, spinal cord and dorsal root ganglia, peripheral
nerves, neuromuscular junction and muscle [2].
Paraneoplastic syndromes (PNS)
PNS are non-metastatic syndromes, particularly remote
effects that are not associated with cancer therapy, coagulopathy,
infection or metabolic causes [3]. Main paraneoplastic
syndromes which may be the consequence of lung
cancers comprise the following: Cerebellar degeneration
(particularly small cell lung cancer), subacute sensory
neuropathy and encephalomyelitis most of which have
small cell lung cancer (SCLC) [4,5]. These patients usually
have anti-Hu antibodies in their serum [6].
Paraneoplastic cerebellar degeneration (PCD)
Paraneoplastic cerebellar degeneration (PCD) is the
most frequently seen paraneoplastic syndrome affecting
the brain. PCD is most commonly associated with cancers
of the ovary, breast, and lung. The anti-Purkinje cell antibodies
(anti-Yo) that specifically damage the Purkinje cells
of the cerebellum are found in the patient’s serum and
cerebrospinal fluid. The typical presentation of PCD includes
limb and truncal ataxia, often along with dysarthria. On
some occasions PCD may be the presenting sign of occult
malignancies [7].
Paraneoplastic limbic encephalitis (PLE)
PLE may occur in isolation or in association with
encephalomyelitis or sensory neuronopathy. PLE is considered
as a rare complication of SCLC [8]. Cognitive decline
as well as personality and mood changes can be seen in
limbic encephalitis [9]. PLE may be a rare neurological
consequence of a variety of cancers, most commonly
originating from lung, breast and testis. The etiology is
believed to be immune-mediated, caused by tumor-induced
autoimmunity launching an attack against one’s own central
nervous system [10]. The patient may present with amnesia,
depression, anxiety, seizures and/or personality changes.
The onset of these symptoms may precede the diagnosis
of malignancy by a period of up to 2 years. The malignancy
may be occult and unless the syndrome is recognized, it
may fail to be detected. The diagnosis of PLE is suggested
by the clinical picture, Magnetic Resonance Imaging (MRI)
evidence of mesial temporal lobe abnormality and cerebrospinal
fluid (CSF) abnormalities such as the presence of
oligoclonal bands. It may be further supported by the
presence of paraneoplastic antibodies in the serum. Immunosuppression
has been tried in some cases but memory
impairment is often irreversible. There are several case
reports in the literature of paraneoplastic limbic encephalitis but few emphasize the resulting impact that this may have
on the patient’s quality of life and their care-givers [10].
Paraneoplastic limbic encephalitis is a challenging and
rare neurological syndrome that demands joint management
by neurologists, oncologists and the palliative care team.
Its prolonged and uncertain course causes distress to the
patient but even more so to their care-givers. Early recognition
of the syndrome is important as this will impose a
thorough investigation for the responsible malignancy and
consequently its early detection and management [10].
Subacute sensory neuronopathy
In subacute sensory neuronopathy, symptoms typically
begin before the cancer is identified, with dysesthetic pain
and numbness in the distal extremities or occasionally in
the arms, face or trunk. The symptoms may be asymmetrical,
all sensory modalities may be affected but motor function
is preserved. Sensory ataxia is usually prominent. A typical
sensory neuropathic pattern is seen in EMG (electromyography)
[2,9].
Anti-Hu-associated paraneoplastic sensory neuropathy
(PSN) is considered an autoimmune disorder involving
both cell-mediated and humoral mechanisms [11]. However,
peripheral nerve microvasculitis in association with anti-
Hu PSN is extremely rare, and only three cases have been
reported in the literature [12]. Generally, the presence of
low titres of anti-Hu antibodies is associated with early
stage, good response to chemotherapy and improved outcome
[13]. It is thought that anti-Hu antibodies play an
important role in tumor suppression [14]. Despite the
favourable survival of these patients, the treatment of PSN
generally remains unsatisfactory. Paraneoplastic encephalomyelitis
(PEM) and paraneoplastic sensory neuronopathy
(PSN) are clinically well-defined, frequently overlapping,
and almost always associated with anti-Hu antibodies (i.e.
type 1 anti-neuronal nuclear autoantibodies) and small-cell
lung cancer [6,15]. The etiology of PEM/PSN syndrome
and other paraneoplastic syndromes is still unknown. The
PEM/PSN syndrome is characterized by a high titer of anti-
Hu IgG antibodies in the serum and CSF, the presence of
inflammatory infiltrates of T cells and B cells in the nervous
system, and the existence of a tumor, usually SCLC [16,17].
These characteristics suggest that a mechanism mediated
by the humoral or cell-mediated immunities may play a
central role in the pathogenesis of this disease. PSN is
sometimes manifested by cranial nerve involvement, seen
as trigeminal, facial, or abducens nerve palsies [15]. However,
only a few cases of PSN with multiple cranial nerve involvement
have been reported.
Neuromuscular junction syndromes
The neuromuscular junction syndromes due to lung
cancer are Lambert-Eaton myasthenic syndrome (LEMS)
and myasthenia gravis (MG). To compare the clinical
features of patients with LEMS associated with carcinoma,
with patients having LEMS but no cancer, reports on LEMS patients were analyzed systematically [18]. Cancer was
detected (CD group) in 62% of the 227 included cases.
This CD group showed a male predominance (70%). No
sex difference was found in patients in whom no cancer
was detected (NCD group). Median age at onset of LEMS
in the CD group was higher than in the NCD group (58
and 49.5 years, p<0.01). Median interval between onset of
symptoms and diagnosis of LEMS was longest in NCD
cases (p<0.001). CD patients had additional immunological
disorders less frequently than NCD cases (6 and 27%,
p<0.001). Symptoms distinguishing the CD group from
the NCD group were weight loss (p<0.001) and need for
prolonged artificial ventilation after anesthesia (p<0.05).
This analysis showed significant differences between CD
and NCD cases of LEMS. The male predominance and
higher age at onset in patients with a tumor probably
reflected the characteristics of patients with SCLC. The
high frequency of additional immunological disorders in
patients without malignancy, together with the younger
age at onset suggested a similar etiology as other nonparaneoplastic
autoimmune diseases [18].
Lambert–Eaton myasthenic syndrome (LEMS)
LEMS is an autoimmune disorder of the presynaptic
neuromuscular junction caused by autoantibodies to the
voltage-gated calcium channels situated at the nerve terminus
[19]. About 60% of patients with LEMS have small
cell lung cancer while the incidence of LEMS in SCLC is
3% [2,20].
LEMS is characterized by lower extremity proximal
weakness and fatigability. Bulbar musculature is not involved.
MG usually affects ocular, bulbar and respiratory
muscles more than extremity muscles. In contradistinction
to LEMS patients, myasthenic patients grow weaker with
exercise [2,21]. LEMS is related with an antibody that
reacts with the PQ-type voltage gated calcium channel.
The same PQ-type voltage-gated calcium channels are
found in small-cell lung cancers, a fact which explains the
relationship between LEMS and SCLC [22].
Other neuromuscular paraneoplastic diseases
Brainstem encephalitis, paraneoplastic non-necrotizing
myelitis, autonomic neuropathy, opsoclonus-myoclonus, anti-Ri syndrome, visual loss due to encephalomyelopathy,
subacute sensory-motor neuropathy and neuromuscular
junction syndromes may be the result of lung cancers [2].
Polymyositis and dermatomyositis are common inflammatory
muscle diseases and both of them may be paraneoplastic,
although dermatomyositis patients are more prone
to cancer [23,24]. Muscle cramps, acquired neuromyotonia,
stiff person syndrome and shoulder-hand syndrome are
other paraneoplastic muscle disorders which may also be
seen in lung cancer patients [2,25]. Many of the diseases
mentioned above mostly need electrophysiological differential
diagnosis under the guidance of a neurologist, preferably
an electromyographer.
Opsoclonus
Opsoclonus is a dyskinesia consisting of involuntary,
arrhythmic, chaotic, multidirectional saccades, without
intersaccadic intervals. In adults, the most common causes
of opsoclonus include parainfectious brainstem encephalitis,
paraneoplastic, and metabolic–toxic states. In many cases,
the cause is never established. Such saccadic oscillations
differ from nystagmus in that the phase that takes the eye
off the target is always a saccade, not a smooth eye movement.
In contrast to ocular flutter, which consists of horizontal
back-to-back saccades, opsoclonus is multidirectional.
The pathogenesis of opsoclonus is uncertain. Damage to
omnipause cells in the brainstem or to the cerebellum has
been implicated. Computer simulation of a saccadic system
model indicated that damage of afferent projections to the
oculomotor region of the fastigial nucleus could generate
opsoclonus [26].
Paraneoplastic neuromyotonia
Neuromyotonia or ‘syndrome of continuous muscle
fiber activity’ is characterized by muscle stiffness at rest
and delayed muscle relaxation after a voluntary contraction
resembling myotonia. Neuromyotonia is due to hyperexcitability
of peripheral motor nerves. Autoimmune etiology
for neuromyotonia has been described with evidence for
autoantibodies directed against voltage-gated potassium
channels of peripheral nerves in some patients [27,28]. The
autoantibodies may be associated with neoplastic lesions.
Paraneoplastic myoclonia
Myoclonia are characterized by sudden involuntary
movements caused by contractions of muscle groups or groups of muscle fibers. In paraneoplastic opsoclonusmyoclonus
syndrome, some patients show antibodies
directed against 55 and 80-kDa antigens on neuronal nuclei
called anti-Ri-antibodies. The association of neuromyotonia,
sensory neuropathy, cerebellar symptoms and myoclonia
with anti-Hu antibodies in a patient with SCLC was reported
by Toepfer et al [29].
The shoulder-hand syndrome
The shoulder-hand syndrome is described by many
authors as a sequela of myocardial infarction, hemiplegia
and cancer of the lungs. The syndrome evolves in a form
that resembles the post-traumatic algodystrophies. Pain,
stiffness, and tenderness of the shoulder with limited
movement, indistinguishable from capsulitis, are usually
the first symptoms, and these sometimes progress to swelling,
pain, stiffness and discoloration of the hand fingers. The
mechanisms of the syndrome probably involve the central
nervous system rostrally to the spinal cord as the syndrome
is never seen in tetraplegic patients. Damaged afferents
may activate sympathetic efferents to well-defined areas.
The fact that the elbow is not involved may be only apparent.
In fact, the other diseases such as tennis elbow, pain of the
hand is very often accompanied by latent myofascial trigger
points of the elbow [25].
ANTIBODIES SUGGESTED FOR PNS
The detection of onconeural antibodies has been very
useful in helping to define the paraneoplastic etiology of
a given neurological syndrome. The presence of anti-Hu
antibodies strongly supports a diagnosis of paraneoplastic
neurological syndrome associated with SCLC [30]. Anti-
Hu reacts with a 35-40 kDa neuronal nucleoprotein. Subacute
sensory neuronopathy (SSN) and paraneoplastic encephalomyelitis
(PEM) are known paraneoplastic complications
associated with anti-Hu antibodies [31,6]. Recently
neoplastic gastrointestinal pseudo-obstruction and LEMS
in association with anti-Hu antibodies were described [32].
Gangliosides may act as onconeural antigens in paraneoplastic
neuropathies in some lung cancers [33] Myelin
glycolipids may also be the target of antibodies in peripheral
paraneoplastic nervous system disorders [34]. Some SCLCs
produce peptide hormones such as ADH (antidiuretic
hormone) and thus cause syndrome of inappropriate ADH
secretion [35].
Onconeural antibodies are detected in many laboratories
by screening of sera on frozen sections of rat or mouse
cerebellum [36]. Positive immunoreactivities are usually
confirmed by immunoblot of recombinant proteins or
neuronal homogenates. Sera from patients with SCLC, the
most common tumor associated with paraneoplastic neurological
syndromes (PNS), sometimes harbor antibodies
against neural antigens that have not previously been
recognized as associated with PNS [37]. When this happens,
it is important first to establish whether the antibody is
related to the presence of a specific type of cancer, and
second to investigate whether the antibody is associated
with a particular PNS. Even if the antibody is not directly
related to the immune response that causes a PNS, it may
indicate the presence of an underlying cancer undiagnosed
at the time of the antibody determination. Very recently, a
new antibody called anti-glial nuclear antibody (AGNA)
has been described in patients with PNS and SCLC and it
has been shown that the antibody is a marker for SCLC
[38]. AGNA has been initially identified in 24 sera by
immunohistochemistry on rat cerebellum. AGNA positive
sera have showed a characteristic nuclear staining of the
Bergmann glia in the Purkinje cell layer. This antibody is
thought to be helpful in the diagnosis of SCLC-related PNS,
particularly the LEMS [38].
The authors concluded that the recognition of AGNA
was helpful since this antibody was found in PNS associated
with SCLC, particularly LEMS, in which other onconeural
antibodies were absent [38].
THERAPEUTIC APPROACH FOR PNS
Lung cancer has the highest incidence of PNS. PNS
management requires specific measures such as presence
of anti-neuronal antibodies which strongly indicate that a
neurological syndrome is paraneoplastic [39,40]. Paraneoplastic
syndromes of lung cancers should be treated by
treating the lung cancer. Symptomatic medications may
also be needed in many of them. Plasmapheresis is being
used with considerable frequency in the management of
malignant and non-malignant disorders. It has been useful
in the management of hyperviscosity and occasionally of
paraneoplastic syndromes [41].
A thorough neurological examination and diagnostic
testing are essential for identifying lung cancer related
neurological disorders, which may sometimes become
diagnostic challenges. Multidisciplinary approach is highly
needed both in the diagnostic and therapeutic approaches.
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