General Principles of Treatment
Given that paraneoplastic disorders are rare conditions and that the range of Ab-associated
syndromes continues to broaden, controlled studies are not available for the majority
of PNS. Most treatment recommendations are based on case series and expert opinions.
Considering the potentially irreversible damage, the treatment of PNS should be started
as early as possible.
Main principles of PNS management include:
-
Detection and resection of the tumor in order to remove the source of peripheral antigen
stimulation;
-
Rapid start of immunosuppressive treatment;
-
Symptomatic treatment.
Prompt and aggressive tumor treatment is the most relevant therapeutic strategy in
PNS.
Tumor detection and efficacy of tumor therapy
In about two thirds of patients with PNS, the tumor is still unknown at the time of
onset of neurological symptoms [1]. Since the PNS-causing immune response slows down cancer growth, the tumors can
be relatively small and difficult to diagnose at the time of initial neurological
manifestation. The presence of multiple Abs in about one third of patients with PNS
helps to focus the diagnostic workup on specific tumors [7]
[9]. PNS are most frequently associated with lung cancer (small cell » non-small cell
lung cancer), ovarial carcinoma and teratoma, breast cancer, Hodgkin’s disease and
non-Hodgkin lymphoma, thymoma, and prostate cancer [1]
[10]. It is also important to rule out testicular tumors in young men and neuroblastoma
in young children. Based on the target antigen and the suspected tumor, a targeted
stepwise diagnostic approach is recommended ([Table 2]) [11]. Should the standard workup yield negative results, it can be supplemented by a
whole-body FDG PET/CT scan. While being an expensive investigation, it offers the
advantage of improving the diagnostic sensitivity [12]. The limitations of FDG PET/CT include false-positive findings in the presence of
inflammatory processes and false-negative findings with tumors exhibiting low proliferation
rates (e. g., differentiated teratomas) or non–metastatic skin cancers. If no tumor
can be detected, the diagnostic workup should be repeated in 3 months’ time and then
every 6 months for a period of at least 4 years [11]. Adequate tumor treatment frequently results in the stabilization or even improvement
of the neurological deficits [13]
[14]
[15]. Close interdisciplinary collaboration is crucial, since tumor resection, especially
in combination with chemotherapy and/or radiotherapy, may be sufficient to control
the PNS.
Table 2 Recommendations for stepwise cancer screening in patients with paraneoplastic syndromes
[1]
[11].
|
Tumor, prevalence#
|
Stepwise diagnosis (sensitivity of test method)
|
|
Lung cancer SCLC 38.4%, NSCLC 7.9%
|
Chest CT scan (80-85%)→FDG PET(CT)→bronchoscopy / EB-US with biopsy
|
|
Ovarian cancer 10.5%
|
Transvaginal US (69-90%), Ca125 (62%)→pelvic/abdominal CT scan→FDG PET (CT)
|
|
Ovarian teratoma#
|
Transvaginal US (58-94%)→pelvic/abdominal CT/MRI (93-96%) →
→ chest CT scan, if required (extrapelvic teratomas)
|
|
Breast cancer 9.7%
|
Mammography, US→breast MRI (71-100%), FDG PET (CT), if required
|
|
Hodgkin’s disease 3.0%, non-Hodgkin’s lymphoma 3.4%
|
Chest/abdomen CT scan, US→FDG PET (CT)
|
|
Thymoma 2.7%
|
Chest CT/MRI (75-90%)→FDG PET (CT)
|
|
Testicular tumors 1.7%
|
US (72%), AFP+β-HCG→pelvic CT/MRI*, biopsy in the case of microcalcifications
|
# Prevalence among all PNSs, based on Euronetwork Database; no data on ovarian teratoma
available
Abbreviations: AFP, alpha fetoprotein; β-HCG, beta human chorionic gonadotropin; CA125,
cancer antigen 125; EB-US, endobronchial ultrasound; US, ultrasound
Principles of immunotherapy
Immunotherapy should be started as early as possible, preferably within 4 weeks of
initial manifestation and before the neurological deficits have reached a plateau
and become irreversible [16]
[17]
[18]. If the suspicion of PNS is clearly supported by clinical evidence, immunotherapy
may be started even without definite tumor diagnosis (exception: suspected lymphoma).
Acute treatment is usually based on either corticosteroid pulse therapy (e. g., 5×1000 mg
methylprednisolone IV, if required with oral tapering) or intravenous immunoglobulin
G (IVIG, e. g., 0.4 g/kg bodyweight for 5 days). Should the patient not improve with
these regimes, treatment escalation to an apheresis therapy (plasma exchange or immunoadsorption)
can be undertaken. Basically, IVIG treatment and apheresis therapies are more effective
in patients with Abs directed against surface antigens compared to intracellular antigens
with mainly T cell-mediated immune responses [3]
[16]
[19]
[20]. If the patient does no improve with acute treatment, an early (typically up to
2 weeks after the above-mentioned primary treatment) escalation to cyclophosphamide
(as a short-term high-dose treatment with 750–1000 mg/m2 IV) or rituximab (e. g., 500 mg IV on days 1 and 15) can be undertaken [16]
[21]
[22]. Here, it is important to ensure that the patient receives appropriate concomitant
medications, such as uromitexan along with cyclophosphamide or steroids and antihistamines
along with rituximab.
Long-term treatment is typically based on classical oral immunosuppressants, such
as azathioprine (2–3 mg/kg/d), mycophenolate mofetil (250–1000 mg b.i.d.) or oral
cyclophosphamide (1–2 mg/kg/d) as a monotherapy or in combination with oral steroids.
Alternatively, rituximab (e. g., every 6 months) or IVIG at regular intervals (usually
every 4 to 8 weeks) may be effective as well.
Special immunotherapeutic and symptomatic treatment strategies for selected PNS
Paraneoplastic Cerebellar Degeneration (PCD)
In the majority of patients with PCD, Abs to intracellular antigens (Yo, Hu, Ri, Tr,
Ma2, CV2/CRMP5, Amphiphysin, GAD, Zic4, ANNA3, PCA-2; sporadically, Homer3, CARPVIII,
PKCγ, Ca/ARHGAP26) are detected, while Abs to surface antigens (VGCC, in combination
with Lambert–Eaton myasthenic syndrome (LEMS); sporadically mGluR1) are rare [23]. The clinical picture is dominated by progressive cerebellar ataxia, reaching a
plateau within the first weeks to months in the majority of patients, with 50-70%
of patients becoming wheelchair-bound during this time [24]. In most cases, irreversible loss of Purkinje cells is the underlying cause of this
condition. The prognosis of patients with Abs to intracellular antigens is particularly
unfavorable (especially, if Hu- or Yo-, CV2/CRMP5-Abs are present) [14]. In some patients, stabilization or slight improvement can be achieved with early
tumor resection, followed by chemotherapy, where indicated [16]. While subsequent immunotherapies, including corticosteroids, IVIG, plasma exchange,
cyclophosphamide and tacrolimus, generally have little effect, individual cases with
relevant treatment response have been reported [16]
[25]
[26]
[27]. Patients with Tr-Abs after successful lymphoma treatment and patients with Ri-Abs
under immunotherapy have a more favorable prognosis [28]
[29]. Overall, response to immunotherapy is better in patients with GAD-Abs; these Abs
are rarely tumor-associated [30]. Steroid pulse therapy and IVIG, plasma exchange, and rituximab may be effective
in these patients. In patients with VGCC-Abs, PCD may occur alone or in combination
with LEMS. In LEMS, the response rate is higher compared with PCD and cerebellar symptoms
stabilize in up to 40% of patients after tumor therapy and immunotherapy [31].
In patients with cerebellar tremor, symptomatic treatment with propranolol (30–180 mg/d),
primidone (30–500 mg/d), topiramate (25–100 mg/d), or clonazepam (1.5–6 mg/d) can
be attempted [32].
Encephalomyelitis and limbic encephalitis (EM, LE)
Apart from so-called “classical” EM and LE (associated with Abs against Hu, Ma, GAD,
CV2/CRMP5), this disease spectrum has been substantially expended over the last decade,
especially with the identification of several Abs to surface antigens (NMDAR, VGKC,
DPPX, AMPAR, GABAbR, dopamine receptor 2, mGluR5). Patients with Abs to surface antigens
have a much better prognosis, except for cases with additional classical paraneoplastic
Abs [33]
[34]. LE is most frequently associated with NMDAR-, LGI1- and Caspr2-Abs; treatment of
these forms of encephalitis will be discussed individually. There are significantly
less data available on LE associated with other Abs to surface antigens. Principles
of therapy of LE with Abs to intracellular antigens are similar to those of classical
PNS (as described above). The prognosis remains poor with the exception of Ma2-Ab-associated
encephalomyelitis in which approx. 30% of patients experience improvement after adequate
tumor treatment and immunotherapy [35].
A. Anti-NMDA receptor encephalitis (anti-NMDAR encephalitis)
Anti-NMDAR encephalitis is the most common type of antibody-mediated encephalitis
and accounts for approx. 4% of all encephalitis cases [36]. Patients with anti-NMDAR encephalitis typically do not experience relevant neuronal
loss, but reversible dysfunction caused by internalization of NMDA receptors from
the cell surface [37]
[38]. This mechanism explains the good outcome, up to complete recovery, in about 75%
of patients after adequate therapy [39]. The acute stage of the disease can last for several months and patients frequently
undergo intensive care unit treatment during this time. Mild cognitive deficits may
persist [40]. Mortality, often caused by intensive care complications, is about 7–9%. Of all
anti-NMDAR encephalitis cases, 38% are paraneoplastic and associated in young women,
very rarely in men, with teratomas, and in patients >45 years with carcinomas [41]. The occurrence of teratomas increases among adolescents and is at 15% in female
patients <14 years, at 30% <18 years and at 60% >18 years [39]. Thus, immediate targeted tumor screening is crucial in patients with anti-NMDAR
encephalitis. Since FDG PET-CT is not sensitive enough to detect well-differentiated
teratomas, a negative scan result is considered inconclusive. Instead it is recommended
to perform an abdominal MRI scan and a thorough gynecological examination, including
endovaginal ultrasound. In children <12 years and in men, anti-NMDAR encephalitis
of paraneoplastic etiology is much rarer.
So far, treatment efficacy data of 4 larger retrospective case series have been published
[42]
[43]
[44]
[45]. Any tumor detected has to be immediately removed. Up to 80% of patients improve
with tumor resection in combination with first-line immunotherapy: steroid pulse therapy,
IVIG or plasma exchange [39]. However, in non-paraneoplastic cases, first-line immunotherapy results in improvement
in only approx. 50% of patients [39]
[44]. Controlled studies comparing the above-mentioned first-line immunotherapies are
not available; however, a small series (n=9) found an advantage for early plasma exchange
treatment [46]. Given the direct pathogenetic role of NMDAR-Abs, the use of apheresis therapy is
very reasonable. The efficacy of immunoadsorption seems to be similar to those of
plasma exchange [47]
[48]. As expected, an early immunotherapy (<40 days after initial manifestation) is associated
with a significantly better prognosis [43]. If no tumor can be detected or the response to treatment is delayed, second-line
therapy with rituximab or cyclophosphamide should be considered [49]. Again, there is a lack of comparative studies. Cyclophosphamide crosses the blood-brain
barrier, but is associated with toxic effects and has a negative impact on fertility
which is highly relevant in young women. For this reason, rituximab continues to be
increasingly used in clinical practice. In approx. 75% of cases, second-line therapy
results in further significant improvement of the symptoms [39]
[42]
[44]
[46]. In several cases and case series successful administration of other immunosuppressants,
including azathioprine, methotrexate and mycophenolate mofetil, has been reported
[49]. However due to lack of systemic studies a definite judgment on the efficacy of
these drugs cannot be given. In individual refractory pediatric cases, intrathecal
administration of methotrexate and methylprednisolone was effective [50]. Of special interest, and reasonable from a pathogenetic perspective, is escalation
therapy with the proteasome inhibitor bortezomib [51]
[52]. Bortezomib results in a targeted reduction of plasma cells and consequently Abs
production. In two case series, female patients with refractory anti-NMDAR encephalitis
showed a significant clinical improvement after the administration of bortezomib and
a rapid decrease in serum NMDAR-Ab-titers [51]
[52].
The recurrence rate of anti-NMDAR encephalitis is in the range of 12–25%; it is higher
in patients with non-paraneoplastic disease compared with patients after teratoma
resection [42]
[44]. In these cases, treatment with a second-line therapy for a limited period of time
(e. g., 2 years) is recommended, even in patients who showed acceptable initial improvement.
Relapses can occur several months to years after the first episode of the disease;
second-line therapies were demonstrated to be effective [44]. The reason why some patients relapse remains unclear. The postulated phenomenon
of epitope spreading has not been confirmed in patients with several recurrences or
poor prognosis [53]. Intra-individual correlation between Ab-titer changes (especially in the CSF) and
prognosis or development of a recurrence was reported [53]. A characteristic feature of the monophasic course is the rapid decline in anti-NMDAR-Ab-titers
in serum and CSF under treatment [43]
[53]. Inter-individually, Ab-titers are higher in patients with teratomas and in patients
with non-paraneoplastic anti-NMDAR encephalitis with poor prognosis [42]
[43]
[53].
B. Anti-VGKC antibody encephalitis (anti-VGKC encephalitis)
Voltage-gated potassium channels (VGKC) are expressed both in the central nervous
system and juxtaparanodally on peripheral motor nerves. In anti-VGKC encephalitis,
autoantibodies are not directed against potassium channels, but against three VGKC-associated
proteins: leucine-rich glioma inactivated-1 (LGI1), contactin-associated protein-like-2
(CASPR2) and contactin-2 [54]
[55]
[56]. The majority of patients (60-80%) are men, mainly in the second half of life. LGI1-Abs
are typically associated with limbic encephalitis, hyponatremia, and in some cases
with faciobrachial dystonic seizures. The latter are characteristic of LGI1 encephalitis,
last only seconds (<3 s) and occur many times a day [57]. At a later stage of disease, patients may develop generalized seizures. Anti-VGKC
encephalitis of paraneoplastic origin is rather rare (0–11%) [54]
[55]. Apart from encephalitis, CASPR2-Abs can cause neuromyotonia (Isaak-Merten’s syndrome)
which is characterized by peripheral motor nerve hyperexcitability. The combination
of encephalitis, neuromyotonia with autonomous involvement, and insomnia is referred
to as Morvan’s syndrome. It is associated with tumors in approx. 20% of cases [58]. It is unknown whether contactin-2-Abs play an independent pathogenetic role, since
they usually occur in combination with anti-LGI1 or anti-CASPR2. The significance
of other anti-VGKC-Abs (LGI1 and CASPR2 negative) also remains unclear. A recent study
found that 38% of these Abs are directed against intracellular epitopes of the Kv1
subunit of the VGKC complex and are presumably of no clinical significance [59].
Overall, patients with anti-VGKC encephalitis have a favorable prognosis: approx.
75% of patients respond to immunotherapy [58]
[60]. However, in contrast to anti-NMDAR encephalitis, neurodegenerative changes occur
in addition to functional disturbances (the latter probably due to reduced AMPA receptor
expression) [61]. Especially in patients with anti-LGI1-Abs, memory impairment and other cognitive
deficits may persist [62]. The few available neuropathological findings show immunoglobulin deposits, partially
with complement activation and moderate lymphocytic infiltration, as well as neuronal
loss in the hippocampus and amygdala [8].
In most cases, symptomatic treatment with anticonvulsants alone is insufficient. In
patients with anti-VGKC encephalitis of paraneoplastic origin, treatment of the underlying
tumor is crucial. Regarding immunotherapy, either corticosteroids (IV or orally),
IVIG or plasma exchange may be used. There are no prospective comparative studies
available. However, some findings indicate that combined and earlier (within the first
2 months after initial manifestation) treatment is associated with a better prognosis
[49]
[63]. A retrospective study (n=14) found that combination therapy of IVIG plus steroids
was superior to steroid monotherapy [64]. In an open prospective study, all patients (n=9) improved when treated with the
combination of plasma exchange, IVIG and steroid pulse therapy followed by oral steroid
treatment [65].
An immediate response to treatment is rarely observed; the majority of patients improve
after several weeks of treatment [66]. In most cases, first a reduction in seizure frequency is noted, while cognitive
deficits tend to respond much later [60]. Other immunotherapeutic agents, such as azathioprine, tacrolimus, mycophenolate
mofetil and rituximab may be tried in refractory cases [49]. Sometimes patients experience relapses, correlating with an increase in Ab-titers
[67].
C. Other types of encephalitis associated with antibodies to surface proteins
Antibodies to DPPX (dipeptidyl-peptidase-like protein 6) were detected in patients
with multifocal central nervous system deficits and dysautonomia. Rarely, they are
associated with lymphomas. In a retrospective case series, immunotherapy (corticosteroids,
IVIG, PLEX alone or combined with rituximab or cyclophosphamide) resulted in improvements
in about two thirds of patients [68]. Due to the limited data available, no conclusions can be drawn regarding the efficacy
of the various treatments.
Encephalitis with AMPAR-Abs (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
receptor) is tumor-associated in about two thirds of cases and characterized by an
aggressive course of disease [69]. Tumor resection in combination with immunotherapy (corticosteroids or IVIG) can
lead to clinical improvement. Relapses are frequent and occur unrelated to tumor recurrence.
In most cases, relapses can be prevented by treatment with rituximab and cyclophosphamide
[34].
Anti-GABAbR-Abs typically cause limbic encephalitis and less often ataxia. In 50%
of cases a tumor (frequently small cell lung cancer) is detected [70]. The combination of tumor resection, chemotherapy and immunotherapy can be effective
(particularly in case of a favorable tumor prognosis) [33].
Encephalitis associated with anti-IgLON5-Abs is a very rare disease of unknown origin.
Patients usually do not respond to immunotherapy, even though IgLON5 is a cell surface
protein [71]. Neuropathology demonstrates a tauopathy involving the midbrain tegmentum and the
hypothalamus. Apart from brain stem and motor symptoms, parasomnia is a typical feature
of the disease.
Opsoclonus-myoclonus syndrome (OMS)
The disease occurs in small children and adults. In contrast to other classical PNS,
OMS may follow a chronic relapsing course. Young children (<5 years) with OMS are
typically seronegative for autoantibodies (except for a few cases with anti-Hu-Abs)
and in approx. 50% of these patients OMS is associated with neuroblastoma [72]. The outcomes achieved with the standard treatments (tumor therapy, corticosteroids
or ACTH in pediatric patients, often combined with IVIG; if required, plasma exchange)
are often unsatisfactory and associated with residual deficits [73]. More aggressive therapeutic strategies, such as rituximab and cyclophosphamide,
can improve long-term prognosis, including cognitive and behavioral deficits [74]
[75].
Among adults, OMS is in approx. 40% of paraneoplastic origin and in 60% idiopathic
or presumably of parainfectious etiology (e. g., associated with HIV, mumps, CMV,
EBV) [76]. In older patients (>50 years) with paraneoplastic OMS, lung cancer or breast cancer
(typically with anti-Ri-Abs) are frequently detected. Other antibodies to intracellular
antigens (Hu, Ma2, amphiphysin, CV2/CRMP5) are less often detected and Abs to surface
antigens (GABAbR, NMDAR, DPPX, and α-GlyR [rather unspecific]) have been described
in isolated cases only. Often adult OMS remains seronegative as well. Following effective
tumor treatment, neurological symptoms may improve [77]. The role of immunotherapy in patients with paraneoplastic OMS remains unclear.
Reports of an effective treatment with corticosteroids, cyclophosphamide, or plasma
exchange are limited to few cases [73]. In younger patients, an association between teratoma, anti-NMDAR-Abs negative encephalitis
(mostly with brain stem involvement) and OMS has been described [78]. After tumor resection and immunotherapy (methylprednisolone, in some cases combined
with IVIG and plasma exchange), 8 of 10 patients became symptom-free and 2 experienced
residual ataxia and dysarthria. Likewise, patients with parainfectious OMS responded
well to immunotherapy (e. g., IVIG) and overall had a better prognosis [77]
[79]. Clonazepam (3×0.5-2 mg/d) or propranolol (3×40–80 mg/d) can be used for symptomatic
treatment.
Stiff-person syndrome (SPS)
In patients with SPS, antibodies to the synaptic vesicle-associated protein amphiphysin
(approx. 2–10% of cases, mostly with breast cancer), the intracellular enzyme glutamic
acid decarboxylase (GAD65, approx. 60–80%, facultative paraneoplastic), or the cell
surface-associated glycine receptor α1 subunit (GlyR, approx. 10%, facultative paraneoplastic)
are detected [80]
[81]
[82]. The hallmark of SPS is generalized muscle rigidity with painful muscle spasms,
an exaggerated startle response and a characteristic gait abnormality with freezing
of gait and hyperlordosis. Symptoms can also be localized and affect one limb only
(stiff-limb syndrome). Apart from classical SPS, anti-GlyR-Abs may occur in patients
with so-called PERM syndrome (progressive encephalomyelitis with rigidity and myoclonus).
Signs of brainstem involvement, primarily eye movement abnormalities, ataxia, as well
as convulsive seizures and autonomic dysregulation, can occur in patients with PERM
syndrome. In contrast to other PNS, most patients with SPS experience a significant
improvement with symptomatic treatment alone, which therefore is used as first-line
therapy. GABA-A receptor agonists such as diazepam (average dose 40 mg/d) or clonazepam
(1–6 mg/d) and GABA-B receptor agonists such as baclofen (average dose 60 mg/d) are
in many cases effective in reducing muscle spasm and rigor; however, tolerance may
develop later [81]. In individual cases, positive effects have been reported for treatment with levetiracetam,
valproate or gabapentin [83]
[84]
[85]. In extremely severe cases, intrathecal baclofen treatment can be used [86]. Besides symptomatic treatment, a long-term immunosuppressive therapy is usually
required. In patients with paraneoplastic SPS (especially breast cancer with amphiphysin-Abs)
cancer treatment, including chemotherapy, has the highest priority. With regard to
immunotherapy, both corticosteroids and immunosuppressants (e. g., cyclophosphamide)
can be effective [80]
[87]
[88]. Remarkably, experimental data has indicated that anti-amphiphysin-Abs may play
a direct pathogenetic role in SPS; up to now, this has not been demonstrated for any
other antibody directed against an intracellular antigen [89]. In SPS patients with anti-GAD-Abs, IVIG (2 g/kg per cycle every 4 weeks) was found
to be effective and is recommended as first-line therapy [81]
[90]. Alternatively, steroid pulse therapy (e. g., methylprednisolone 500 mg IV for 5
days) with subsequent switch to oral prednisone, gradually tapered off to a maintenance
doses of 5–10 mg/d, is recommended [91]. However, the use of steroids is limited in many cases by diabetes, a common comorbidity,
necessitating treatment with steroid-saving medications, such as mycophenolate mofetil,
azathioprine, or cyclophosphamide. Treatment escalation to apheresis therapy can be
effective, regardless of the type of antibody. In SPS patients who tested positive
for anti-GAD-Abs, plasma exchange treatment achieved a significant improvement of
symptoms in approx. half of the patients, even in some patients who did not respond
to first-line therapy [92]. While rituximab was reportedly effective in individual cases, a smaller blinded
study failed to show a convincing effect of rituximab [81]
[93]. As a general rule, treatment of SPS should be started as early as possible, before
the patient develops irreversible tissue damage. According to a large retrospective
study (n=99), relevant improvement of symptoms can be achieved during the first year
after initial manifestation only [81].
Patients testing positive for anti-glycine receptor α1-Abs generally have a better
prognosis and respond well to immunotherapy [82]. Similar to anti-NMDAR encephalitis, internalization of the glycine receptor is
discussed as the underlying pathogenetic mechanism. Relapses occur in approx. 10%
of cases [82]. A lethal outcome is rare and may occur in rapidly developing courses with autonomic
involvement during the acute stage of disease. For most cases, successful treatment
with steroid therapy (initially as a pulse therapy, with later switch to oral prednisone)
in combination with plasma exchange and/or IVIG has been reported.
Paraneoplastic myelopathy (PM)
Paraneoplastic myelopathy or myelitis is a rare disease which may remain unrecognized
until late in the course of the disease. Clinically, PM presents as a subacute or
slowly progressive myelopathy which may initially be misdiagnosed as a seronegative
NMOSD or PPMS [94]. PM is usually associated with anti-amphiphysin- or anti-CV2/CRMP5-Abs. Less frequently,
other antibodies directed against intracellular antigens (Hu, Ri, Yo, Ma1/2, GAD,
PCA2, ANNA3) or surface antigens (VGCC, VGKC, glycine receptor α1 subunit) are detected.
In rare cases, especially in elderly patients, anti-AQP4-Abs may be induced by a tumor,
presenting a paraneoplastic form of neuromyelitis optica spectrum disorder [95]
[96]. No clinical studies evaluating the efficacy of PM treatments are available. The
prognosis is unfavorable in the majority of cases. In a cases series, transient improvement
was achieved in 8 of 26 patients, but only 3 patients experienced long-lasting independent
mobility [94]. In individual cases, corticosteroids or cyclophosphamide were effective [97]
[98].
Paraneoplastic polyneuropathy (pPNP)
The disease often precedes clinical tumor manifestation [73]. Onconeural Abs can be detected in 80% of patients, primarily anti-Hu- (frequently
associated with lung cancer) or anti-CV2/CRMP5-Abs (with lung cancer, thymoma, or
neuroendocrine tumors). Peripheral involvement in combination with the corresponding
characteristic central PNS may occur along with anti-amphiphysin-, anti-Yo-, anti-Ri-,
anti-Tr-, or anti-PCA2-Abs [99]. Damage of peripheral sensory ganglia results in subacute sensory, often asymmetric
polyneuropathy with pain, paresthesia and sensory ataxia (classical subacute sensory
polyneuropathy). Patients with autonomic involvement develop orthostatic hypotension,
impotence, anhidrosis, and sicca syndrome. Sensorimotor polyneuropathy may occur as
well. Electroneurography helps to reveal axonal and demyelinating variants. CSF analysis
frequently shows moderately increased protein levels and intrathecal immunoglobulin
G synthesis, so that the patient may be misdiagnosed as having CIDP. Generally, immunotherapy
has little effect in patients with pPNP [17]. In a large study with anti-Hu-associated paraneoplastic encephalomyelitis and polyneuropathy
(n=200), tumor therapy was the only treatment associated with stabilization of the
neurological deficits [13]. Neuropathic pain can be treated with pregabalin (75–600 mg/d), gabapentin (300–3600 mg/d)
or carbamazepine (200–1200 mg/d), if required in combination with amitriptyline (25–75 mg/d).
Apart from classical onconeural antibodies, polyneuropathic syndromes occur with VGCC-Abs,
VGKC-Abs and Abs to ganglionic nAChRs. Ganglionic nAChR-Abs are in 30% of paraneoplastic
origin and can cause both dysautonomia and polyneuropathy [100]. Combined tumor treatment and immunotherapy (e. g., prednisone alone or plus azathioprine)
can improve dysautonomia. In non-paraneoplastic cases, initial IVIG therapy, if required
with further escalation to plasma exchange, and immunosuppression with azathioprine
or mycophenolate mofetil can be effective [101].
Lambert-Eaton myasthenic syndrome (LEMS)
LEMS is associated with lung cancer and antibodies to P/Q-type VGCC in 50–60% and
85% of cases, respectively [102]. Furthermore, LEMS can be triggered by prostate cancer or thymoma. While LEMS is
usually tumor-associated in male patients >40 years, it is typically of autoimmune
origin in younger female patients. Patients testing positive for anti-SOX1-Abs usually
have lung cancer (95% specificity). The presynaptic dysfunction caused by anti-VGCC-Abs
results in a reduced release of acetylcholine at the motor endplate and muscarinic
synapses of the autonomic nervous system. From this, the classical LEMS symptoms can
be derived: generalized muscle weakness (often more pronounced in the proximal legs),
reduced tendon reflexes, fatigue, and autonomic changes (dry mouth, constipation,
impotence, etc.).
Management of paraneoplastic LEMS is based on tumor therapy, including tumor resection
and chemotherapy, which may also have an immunosuppressant effect. Symptomatic therapy
alone can improve neuromuscular transmission at a clinically relevant level. 3,4-diaminopyridine
augments the release of acetylcholine und can be gradually increased (WARNING: side
effects such as epileptic seizures and arrhythmias ) up to the target dose (4×10 mg/d
- 5×20 mg/d) [103]. In refractory cases pyridostigmine (3×30 mg/d–6×60 mg/d), a drug with post-synaptic
action, can be added to the treatment regimen. If response to this treatment is inadequate,
prednisone can be used in combination with azathioprine; in severe cases, escalation
to repeated IVIG therapy or plasma exchange is an option [102]. The prognosis of tumor-associated LEMS is significantly poorer than that of the
autoimmune type.
Paraneoplastic myositis
Apart from dermatomyositis, which is in 30% of cases of paraneoplastic origin, polymyositis
and necrotizing myositis can occur in tumor patients. According to a recent meta-analysis,
factors associated with a paraneoplastic etiology of myositis include advanced age,
male gender, skin necrosis, and dysphagia [104]. Detection of anti-155/140-Abs in cases with negative classical Abs (anti-Jo-1,
anti-PM-Scl, anti-U1-RNP, anti-U3-RNP, anti-Ku) is in 94% associated with a paraneoplastic
origin [105]. While anti-synthetase-Abs are typically associated with autoimmune etiology, their
detection does not reliably rule out a paraneoplastic origin of the disease [106]. Dermatomyositis occurs most frequently with ovarian cancer, breast cancer, lung
cancer, pancreatic cancer, stomach cancer or colorectal cancer, while polymyositis
is associated with lung cancer, bladder cancer or lymphoma [107]. Assumingly, the immunological cross-reaction between undifferentiated myoblasts
and tumor cells is triggered by the expression of identical antigens [108]. The courses of the both diseases are linked: while tumor recurrence is frequently
associated with deterioration of the muscle disease, effective tumor treatment results
in an improvement of muscle strength [109].
The immunotherapy of first choice are glucocorticosteroids (initially 1–2 mg/kg for
2–4 weeks; alternatively, in severe cases initially as a pulse therapy (500 mg IV
for 3–5 days, followed by gradual oral tapering). For relapse prevention, long-term
treatment for 1-3 years with low-dose prednisone in combination with azathioprine
(2–3 mg/kg) or methotrexate (7.5–25 mg/week) is recommended [110]. If response to these treatments is inadequate, IVIG (1-2 g/kg/cycle every 6–8 weeks)
can be added. For refractory cases, rituximab (2×1000 mg IV at intervals of 2 weeks),
mycophenolate mofetil (2 g/d) or cyclophosphamide (1-2 mg/kg/d orally or 0.5–1.0 g/m2 body surface area i. v. per treatment cycle) should be taken into consideration.
The differential diagnosis of patients deteriorating under long-term treatment includes
steroid myopathy; thus, an attempt to reduce the steroid dose should be made. If electromyography
shows abnormal spontaneous activity, steroid myopathy is rather unlikely.
