Co-existence of Lambert-Eaton myasthenic syndrome and subacute cerebellar degeneration in a patient with rheumatoid arthritis

A 38 year old woman with rheumatoid arthritis had a rare co-existence of Lambert-Eaton myasthenic syndrome and subacute cerebellar degeneration. She had mild but transient improvement in muscle power following plasmapheresis, which correlated with the degree of increment on high rate repetitive nerve stimulation (RNS). Her cerebellar signs did not improve, however. This differential therapeutic response may be due to different mechanisms of injury and tissue susceptibility.     

Coexistence of Lambert-Eaton myasthenic syndrome and subacute cerebellar degeneration: differential effects of treatment

A 61-year-old woman presented with two paraneoplastic neurologic disorders--Lambert-Eaton myasthenic syndrome (LEMS) and subacute cerebellar degeneration (SCD)--that antedated the diagnosis of small-cell carcinoma of the lung by 15 months. Plasmapheresis initiated before the identification of the tumor had a beneficial effect on LEMS but did not affect the SCD. Chemotherapy administered for treatment of the primary tumor was also associated with improvement of LEMS but, like plasmapheresis, had no effect on SCD. While the pathogenesis of both LEMS and SCD is thought to be mediated predominantly by humoral immune factors, a differential therapeutic response indicates that mechanisms of tissue damage or susceptibility to tissue injury, or both, differ in these two disorders.     

A case of small cell carcinoma of the lung associated with paraneoplastic cerebellar degeneration and Lambert-Eaton myasthenic syndrome]

A 51-year-old male who showed severe ataxia, dysarthria, bilateral blepharoptosis, diplopia and nystagmus with the subacute onset was reported. The chest roentgenogram and CT scan revealed mass lesions at the hilus of the left lung. The tumor markers, NSE and ProGRP, were elevated; 12.8 ng/ml (< or = 10) and 140.7 pg/ml (< or = 46), respectively. The biopsy was performed surgically and the small cell carcinoma of the lung was confirmed pathologically. His cerebellar symptoms were considered to be caused by the paraneoplastc cerebellar degeneration. However, the blepharoptosis was peculiar. The electrophysiological studies were carried out The muscle strength test of the right APB muscle was 5. But the supramaximum stimulation of the right median nerve evoked only 2.0 mV of CMAP of the right APB muscle. The repetitive stimulation tests of the same nerve showed that 3 Hz stimulation resulted in 42% waning but 20 Hz stimulation evoked no waxing. The post-exercise test of the right APB muscle showed 73% increase of the CMAP. These findings indicated that he also suffered from Lambert-Eaton myasthenic syndrome. The titer of the antibody against the P/Q type voltage-gated calcium channel (VGCC) was remarkably elevated, 1,920 pM. None of the following antibodies were detected ; they included antibodies against acetylcholine receptor, Hu, Yo, Ri, Ma-2, CRMP-5, amphiphysin and glutamic acid dehydrogenase. The small cell carcinoma was treated with the combination of irinotecan hydrochloride and cisplatin, leading to the reduction of the mass lesions and the tumor markers. His cerebellar symptoms improved slightly but his blepharoptosis was unchanged. The titer of antibody against the P/Q type VGCC reduced remarkably to 451.8 pM. We reviewed reported cases associated with paraneoplastic cerebellar degeneration and Lambert-Eaton myasthenic syndrome and discussed the relation between the paraneoplastic syndromes and autoantibodies.     

Transient subacute cerebellar ataxia in a patient with Lambert-Eaton myasthenic syndrome after intracranial aneurysm surgery

Several reports have presented patients with subacute cerebellar ataxia (CA) and Lambert-Eaton myasthenic syndrome (LEMS). Some clinical features of those patients have been described in the previous reports, manifestation of subacute CA prior to LEMS or a co-existence of both diseases, a high incidence of malignancy, and less efficacy of the treatment for subacute CA compared with that for LEMS. Cerebellar ataxia in some patients with LEMS has been suggested to be caused by antibodies to P/Q-type voltage-gated calcium channels (VGCCs). We report herein a patient with subacute CA and LEMS. Cerebellar ataxia appeared 15 months after the occurrence of LEMS, and the onset of CA was thought to be due to serum anti-P/Q-type VGCC antibodies. The clinical course of this patient was atypical, as follows: (1) LEMS preceded subacute CA, which developed after intracranial aneurysm surgery, (2) no malignancy was detected when both diseases co-existed, (3) symptoms of LEMS did not progress with the onset of CA, and (4) there was a definite improvement in symptoms of CA and ¹²³I-IMP SPECT imaging findings after steroid administration. In addition, it is remarkable that LEMS became aggravated in electrophysiologic examinations, in contrast to subacute CA. We suggest that these atypical features of subacute CA and the changes in LEMS may be associated with a balance between the amount of serum anti-P/Q-type VGCC antibodies and the susceptibility of the cerebellum and presynaptic nerve terminals to the antibodies. More cases are needed to investigate the mechanisms involved. The subacute CA and LEMS in this patient have remained comparatively silent after the withdrawal of steroids, and we are continuing to observe her condition.     

Lambert-Eaton myasthenic syndrome has a more progressive course in patients with lung cancer

We studied whether a difference exists in the development of symptoms of the Lambert-Eaton myasthenic syndrome (LEMS) between patients with or without small cell lung cancer (SCLC). We assessed symptoms in 38 LEMS patients, 13 with SCLC, by interviewing them using a structured checklist, backed up by a review of their clinical records, and compared the frequency and time scale of symptoms during the course of LEMS. Bulbar (87%) and autonomic (95%) symptoms for the whole group were more common than reported in the literature. Frequencies of symptoms did not differ significantly between patients with and without SCLC, but symptoms in patients with SCLC appeared within a shorter time-frame, indicating a more rapid clinical course. The presence of a particular symptom associated with LEMS did not predict the presence of SCLC, but in patients with rapidly progressive LEMS the possibility of underlying lung cancer should be of particular concern.     

Paraneoplastic cerebellar degeneration. III. Cerebellar degeneration, cancer, and the Lambert-Eaton myasthenic syndrome.

We studied nine patients with a subacute onset of a pancerebellar syndrome. Six had known cancer (three small-cell carcinoma of the lung [SCLC], one metastatic small-cell carcinoma, one small-cell carcinoma of the prostate, and one non-Hodgkin's lymphoma). Six of eight who had neurophysiologic testing, including the three patients without detectable cancer, had coexistent Lambert-Eaton myasthenic syndrome (LEMS). In two of the patients, LEMS was discovered only by neurophysiologic testing. We looked for anti-Purkinje cell autoantibodies in all patient's sera and in four patients' CSF. We also looked for autoantibodies to voltage-gated calcium channels (VGCCs) in seven patients' sera and two patients' CSF, using the 125I-omega-conotoxin radioimmunoassay. We were unable to detect anti-Purkinje cell autoantibodies in any patients' serum or CSF. However, there were raised titers of anti-VGCC autoantibodies in five of seven patients' serum, including one patient with SCLC who did not have LEMS, and in the CSF of one of two patients. We conclude that the frequency of presentation of a pancerebellar syndrome with LEMS is higher than expected by chance and is usually associated with cancer. In some of these patients, LEMS may be clinically occult. The presence of LEMS and raised titers of anti-VGCC autoantibodies in some patients with subacute cerebellar degeneration is suggestive of an autoimmune etiology even though anti-Purkinje cell antibodies could not be detected. Anti-VGCC autoantibodies are not confined to LEMS. They may be found at high titer in CSF as well as serum.     

Small cell lung cancer with Lambert-Eaton myasthenic syndrome

Four of 69 cases of small cell lung cancer (SCLC) showed evidence of Lambert-Eaton myasthenic Syndrome (LEMS) were studied neurologically and neurophysiologically in four years. The LEMS appearance were preceded that of SCLC in 3 cases for two years at most. Repeated stimulation of ulnar nerve examination showed diminished amplitude of initial response (0.2-0.9 mv); Amplitude of the response at 3 c/s stimulation for 3 sec was diminished 20-63%. (control 3% decreases-13% increases) but that at 20 c/s stimulation for 10 sec increased 200-800% increases. (control: 20% decreases-56% increases). These findings were important for diagnosis of LEMS. The abnormalities of neurotransmission seems to be due to inadequate release of acetyl choline from nerve terminals at abnormal active zone of Ca++ channels.     

Lambert-eaton myasthenic syndrome immunoglobulins react with multiple types of calcium channels in small-cell lung carcinoma

Barium currents through voltage-gated calcium (Ca²⁺) channels were studied in the small-cell lung carcinoma cell line NCI-H345 using patch clamp techniques. Pharmacological dissection of whole-cell barium currents revealed that 23% of the current was sensitive to nitrendipine, 35% to ω-conotoxin GVIA, and between 10 and 39% to ω-Aga-IVA. This implies that these cells express L-, N-, and P-type calcium channels. Only large cells expressed current that was sensitive to ω-Aga-IVA. The size dependency of this P-type channel expression may reflect the cell cycle stage. Cell-attached recordings revealed three unitary conductances: 5 to 6 pS, 10 to 12 pS, and 20 to 23 pS. The largest conductance channel (20-23 pS) was sensitive to bay K 8644 and is presumed to represent L-type calcium channels. The frequency of observing the medium conductance channel (10-12 pS) was reduced by exposure to ω-conotoxin GVIA and may represent N-type channels. Incubation of cells with Lambert-Eaton myasthenic syndrome IgG for 24 to 48 hours removed up to 71% of the whole-cell current. Incubation with control human IgG (normal or myasthenia gravis) had no effect. Lambert-Eaton maysthenic syndrome IgG did not selectively target one “presynaptic” type of calcium channel, but rather appeared to target many of the calcium channel types that are expressed on small-cell lung carcinoma cells.     

Acute onset paraneoplastic cerebellar degeneration in a patient with small cell lung cancer

A patient with small cell lung cancer presented with a rare presentation of an acute onset pancerebellar dysfunction. His clinical condition markedly improved following the surgical removal of the tumor and chemo- and radiotherapy.     

Meningo-myelitis with a favorable course after measles vaccination

A 27 year-old woman complained of symptoms and signs due to a meningo-myelitis, 5 days after anti-rubella vaccination. Among the earliest symptoms she experienced pain and sensory deficit in the inoculated arm. The disease worsened until the 15th day, then improved spontaneously.     

Reduction of P/Q-type calcium channels in the postmortem cerebellum of paraneoplastic cerebellar degeneration with Lambert-Eaton myasthenic syndrome

The aim of this study was to clarify whether autoimmunity against P/Q-type voltage-gated calcium channels (VGCCs) in the cerebellum was associated with the pathogenesis of paraneoplastic cerebellar degeneration (PCD) with Lambert-Eaton myasthenic syndrome (LEMS). We used human autopsy cerebellar tissues from three PCD-LEMS patients and six other disease patients including one with LEMS as the controls. We compared cerebellar P/Q-type VGCC in these patients and controls for the amount and ratio of autoantibody-channel complex using an 125I-omega-conotoxin MVIIC-binding assay with Scatchard analysis, and their distribution using autoradiography. The quantity of cerebellar P/Q-type VGCC measured by Scatchard analysis were reduced in PCD-LEMS patients (63.0 +/- 7.0 fmol/mg, n = 3), compared with the controls (297.8 +/- 38.9 fmol/mg, n = 6). The ratio of autoantibody-VGCC complexes to total P/Q-type VGCCs measured by immunoprecipitation assay were increased in PCD-LEMS patients. We analysed cerebellar specimens by autoradiography using (125)I-omega-conotoxin MVIIC, which specifically binds to P/Q-type VGCCs. In PCD-LEMS cerebellum, the toxin binding sites of P/Q-type VGCCs were markedly reduced compared with controls, especially in the molecular layer, which is the richest area of P/Q-type VGCCs in the normal cerebellum. This suggests that P/Q-type VGCCs of the cerebellar molecular layer is the immunological target in developing PCD-LEMS.     

A case of paraneoplastic cerebellar degeneration with resting tremor]

A 65-year-old woman was operated for gastric adenocarcinoma in 1989. Six years later, peritonitis carcinomatosa, swelling of periaortic lymphnodes and high serum CA-125 were discovered. She received chemotherapy with 5-FU and cisplatin resulting in reduction of ascites. In September, 1998, the swelling of left supraclavicular lymphnodes and the elevation of serum CA-125 reappeared. Pathological diagnosis of supraclavicular lymphnodes was adenocarcinoma. Serum CA-125 was normalized by chemotherapy using cisplatin, farumorubicin and endoxan. However, unsteadiness appeared since December 10, 1998 followed by dysarthria and involuntary movement of neck and upper limbs. These symptoms progressed subacutely. The physical examination on admission revealed swelling of left suraclavicular lymphnodes, nystagmus on lateral gaze, saccadic eye movement on smooth pursuit and severe cerebellar ataxia. In addition, resting tremor of 3-4 Hz was observed at right hand, left wrist and neck which tended to increase amplitude by calculation. Similar movements were seen in the left first toe, though the frequency was lower. Brain MRI revealed mild cerebellar atrophy. She was diagnosed as paraneoplastic cerebellar degeneration (PCD) by serum anti Yo antibody and clinical course. The study of HLA showed positive link to A4 without A24. The primary focus of adenocarcinoma in cervical lymphnodes was suggested to be ovary rather than stomach due to the pattern of immunostaining for cytokeratin, CEA and CA125, although no carcinoma was found in ovarium clinically. The feature of this case is a PCD with resting tremor of frequency of 3-4 Hz and negative link to HLA-A24 in Japanese.     

Protein kinase Cgamma autoimmunity in paraneoplastic cerebellar degeneration and non-small-cell lung cancer

Background

The clinical and immunological profiles of patients with paraneoplastic cerebellar degeneration (PCD) and non‐small‐cell lung cancer (NSCLC) are not well known.

Objective

To review the clinical and immunological features of patients with PCD, NSCLC and without well‐characterised onconeural antibodies.

Methods

The clinical features of nine patients with the diagnosis of classical PCD and NSCLC, included in our archives, were retrospectively reviewed. The presence of antibodies to cerebellar components was determined by immunohistochemistry and immunoblot of rat cerebellum. A cDNA library of human cerebellum was screened with the positive sera to identify the antigen.

Results

Nine patients with PCD and NSCLC were identified. Six patients were men, and the median age at diagnosis of PCD was 63 (range 47–73) years. PCD was completely reversed in two patients, and partially in one, after treatment of the tumour. The serum of one of the patients with PCD showed a unique reactivity with Purkinje cells. The screening of a cerebellar‐expression library resulted in the isolation of protein kinase Cγ (PKCγ). PKCγ immunoreactivity was not observed in the serum of 170 patients with non‐paraneoplastic neurological syndromes, 27 patients with PCD, no onconeural antibodies and small‐cell lung cancer, and 52 patients with NSCLC without paraneoplastic neurological syndromes. The NSCLC from 11 patients without PCD did not express PKCγ at either the RNA or protein level. However, many cells of the NSCLC of the patient with PKCγ antibodies expressed PKCγ.

Conclusion

PCD occurs in patients with NSCLC without typical onconeural antibodies and is associated with immune reactions against key proteins of the Purkinje cells.Paraneoplastic cerebellar degeneration (PCD) is characterised by selective damage to the Purkinje cells of the cerebellum, which usually causes a severe pancerebellar syndrome.¹ In patients with lung cancer, PCD is almost always associated with small‐cell lung cancer (SCLC).² Patients with non‐small‐cell lung cancer (NSCLC) and PCD usually harbour onconeural antibodies typically associated with SCLC in the serum and cerebrospinal fluid, which probably indicate a common immune‐mediated mechanism of neuronal damage.^3,4 Although a few studies have indicated the occurrence of PCD in patients with NSCLC and no onconeural antibodies, these patients were usually included in larger series of patients with PCD with different tumours^2,5,6,7 or were reported as single observations.⁸In this study, we describe the clinical and immunological findings of a series of patients without previously characterised onconeural antibodies who presented with PCD associated with NSCLC.