Voltage gated calcium channel antibody-related neurological diseases.

Voltage gated calcium channel (VGCC) antibodies are generally associated with Lambert-Eaton myasthenic syndrome. However the presence of this antibody has been associated with paraneoplastic as well as non-paraneoplastic cerebellar degeneration. Most patients with VGCC-antibody-positivity have small cell lung cancer (SCLC). Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease of the presynaptic part of the neuromuscular junction. Its classical clinical triad is proximal muscle weakness, areflexia and autonomic dysfunction. Fifty to sixty percent of LEMS patients have a neoplasia, usually SCLC. The co-occurrence of SCLC and LEMS causes more severe and progressive disease and shorter survival than non-paraneoplastic LEMS. Treatment includes 3,4 diaminopyridine for symptomatic purposes and immunotherapy with prednisolone, azathioprine or intravenous immunoglobulin in patients unresponsive to 3,4 diaminopyridine. Paraneoplastic cerebellar degeneration (PCD) is a syndrome characterized with severe, subacute pancerebellar dysfunction. Serum is positive for VGCC antibody in 41%-44% of patients, usually with the co-occurrence of SCLC. Clinical and electrophysiological features of LEMS are also present in 20%-40% of these patients. Unfortunately, PCD symptoms do not improve with immunotherapy. The role of VGCC antibody in the immunopathogenesis of LEMS is well known whereas its role in PCD is still unclear. All patients presenting with LEMS or PCD must be investigated for SCLC.

Related papers:

title: Passive transfer of Lambert-Eaton myasthenic syndrome with IgG from man to mouse depletes the presynaptic membrane active zones.
abstract: In the Lambert-Eaton myasthenic syndrome (LEMS), there is a decreased release of acetylcholine quanta from the nerve terminal by nerve impulse. Recently, an autoimmune origin of LEMS was documented by passive transfer of its electrophysiologic features from man to mouse with IgG. Freeze-fracture electron microscopy of LEMS neuromuscular junctions has revealed a paucity of presynaptic membrane active zones. Thus, the active zones might be the targets of the pathogenic autoantibodies in LEMS. To test this assumption, freeze-fracture electron microscopic studies were done in mice injected with 10 mg of IgG daily from each of three LEMS patients and in control mice treated with normal human IgG or no IgG. IgG from patients 1 and 2 impaired neuromuscular transmission in mice, but IgG from patient 3 failed to do so. After 52-69 days of treatment, diaphragm or anterior tibial muscles were removed and coded. Paired muscles from control mice and mice receiving LEMS IgG were studied "blindly." Satisfactory freeze-fracture replicas of 185 presynaptic membrane P-faces were analyzed by stereometric methods. In mice treated with LEMS IgG that was pathogenic by electrophysiologic criteria, there was a selective depletion of active zones and active-zone particles but not of other membrane particles and there was a concomitant increase of large membrane particles aggregated into clusters. These findings provide additional evidence that the active zones facilitate quantal transmitter release by nerve impulse, lend further support to the assumption that the active-zone particles are Ca2+ channels, and establish mediation of the membrane lesions in LEMS by IgG.

title: Calcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes.
abstract: Voltage-gated calcium channels in small-cell lung carcinomas may initiate autoimmunity in the paraneoplastic neuromuscular disorder Lambert-Eaton syndrome. The calcium-channel subtype that is responsible is not known.



We compared the effects of antagonists of L-type, N-type, and P/Q-type neuronal calcium channels on the depolarization-dependent influx of calcium-45 in cultured carcinoma cells. Serum samples from patients with various disorders were tested for reactivity with P/Q-type channels solubilized from carcinoma and cerebellar membranes and N-type channels from cerebral cortex.



P/Q-type calcium-channel antagonists were the most potent inhibitors of depolarization-induced 45Ca influx in cultured small-cell carcinoma cell lines. Anti-P/Q-type calcium-channel antibodies were found in serum from all 32 patients with Lambert-Eaton syndrome and a diagnosis of cancer and in 91 percent of the 33 patients with Lambert-Eaton syndrome without cancer. Anti-N-type calcium-channel antibodies were found in 49 percent of the 65 patients with the Lambert-Eaton Syndrome. Lower titers of anti-P/Q-type and anti-N-type calcium-channel antibodies were found in 54 percent of 70 patients with a paraneoplastic encephalomyeloneuropathic complication of lung, ovarian, or breast carcinoma, 24 percent of 90 patients with cancer but no evident neurologic complications, 23 percent of 78 patients with sporadic amyotrophic lateral sclerosis, and less than 3 percent of 69 patients with myasthenia gravis, epilepsy, or scleroderma.



The high frequency of P/Q-type calcium-channel antibodies found in patients with Lambert-Eaton syndrome implies that antibodies of this specificity have a role in the presynaptic pathophysiology of this disorder.

title: P/Q type calcium-channel antibodies in paraneoplastic cerebellar degeneration with lung cancer
abstract: Raised levels of P/Q type voltage-gated calcium-channel (VGCC) antibodies were found in 16 (41%) of 39 patients with paraneoplastic cerebellar degeneration (PCD) and Hu antibodies were found in nine (23%). Seven of the 16 VGCC antibody-positive patients had Lambert–Eaton myasthenic syndrome (LEMS). Seven of 15 CSF samples had VGCC antibodies, with evidence of intrathecal synthesis in four. VGCC antibodies should be looked for in PCD, even if there are no symptoms of LEMS, and may be related to the cerebellar dysfunction.

title: Small-cell lung cancer, paraneoplastic cerebellar degeneration and the Lambert-Eaton myasthenic syndrome.
abstract: Several cancers, especially lung, ovarian and breast, can cause paraneoplastic cerebellar degeneration. The presence of different antineuronal antibodies associated with different cancers and paraneoplastic cerebellar degeneration suggests that several immunological mechanisms may result in the same neurological disorder. In patients with small-cell lung cancer, paraneoplastic cerebellar degeneration may occur with or without Hu antineuronal antibodies (HuAb), indicating that patients with the same tumour can develop paraneoplastic cerebellar degeneration by different immunological mechanisms. Furthermore, paraneoplastic cerebellar degeneration sometimes occurs in association with the Lambert-Eaton myasthenic syndrome. In order to try to understand the clinical implication of antineuronal antibodies in patients with small-cell lung cancer, we examined the serum of 57 patients with presenting symptoms of paraneoplastic cerebellar degeneration for the presence of HuAb and P/Q- and N-type voltage-gated calcium channel antibodies. Patients with paraneoplastic cerebellar degeneration who were HuAb positive were compared with HuAb negative patients with respect to neurological symptoms, course of the neurological disorder, response to treatment, tumour prognosis, pathological findings, and cause of death. The tumour outcome and serological findings of these patients were also compared with those of 109 small-cell lung cancer patients without paraneoplastic syndromes of the CNS. Titres of HuAb were classified as 'high' (immunoblot titre > 1:10,000) or 'low' (< 1:10,000), the latter similar to the antibody titres detected in some small-cell lung cancer patients without paraneoplastic symptoms. Twenty-five patients with paraneoplastic cerebellar degeneration (44%) had high titres of HuAb, four (7%) had low titres of HuAb, and 28 (49%) were HuAb negative; for clinical comparisons with the patients with high titres of HuAb, the four patients with low antibody titres were included in the HuAb negative cohort. None of the 109 small-cell lung cancer patients without paraneoplastic symptoms had high titres of HuAb. The presence of high titres of HuAb defined a subset of patients who differed from the HuAb negative paraneoplastic cerebellar degeneration cohort, HuAb positive patients were more likely to be female (P < 0.01), to have multifocal neurological disease (brainstem encephalopathy and sensory neuropathy being common extracerebellar manifestations) (P < 0.002), and be severely disabled (P < 0.005). A total of nine patients (16%) from both paraneoplastic cerebellar degeneration groups developed electrophysiologically confirmed Lambert-Eaton myasthenic syndrome. Seven of these nine patients had serum available for P/Q-type voltage-gated calcium channel antibody testing and all seven were positive. In addition, 20% of HuAb negative paraneoplastic cerebellar degeneration patients without clinically identified Lambert-Eaton myasthenic syndrome had P/Q-type voltage-gated calcium channel antibodies, while only 2% of small-cell lung cancer patients without paraneoplastic symptoms had these antibodies. Treatment of the tumour and/or immunomodulation did not alter the course of paraneoplastic cerebellar degeneration, but improved Lambert-Eaton myasthenic syndrome symptoms. At the time of death, in 60% of HuAb positive and 20% of HuAb negative paraneoplastic cerebellar degeneration patients, the tumour was either not evident or localized to the chest (P < 0.007); neurological disease was the cause of death of 65% HuAb positive paraneoplastic cerebellar degeneration and 10% HuAb negative paraneoplastic cerebellar degeneration patients (P < 0.001).

title: Antibody Repertoire in Paraneoplastic Cerebellar Degeneration and Small Cell Lung Cancer
abstract: The goal of this study is to determine whether patients with paraneoplastic cerebellar degeneration (PCD) and small-cell lung cancer (SCLC) have a specific repertoire of antibodies, if SOX1 antibodies (SOX1-ab) can predict the presence of SCLC, and if antibodies to cell surface antigens occur in this syndrome. Antibody analysis was done using immunohistochemistry on rat brain, immunoblot with recombinant antigens, screening of cDNA expression libraries, and immunolabeling of live neurons in 39 patients with PCD and SCLC. VGCC-ab were measured by RIA, and SOX1-ab, Hu-ab, and ZIC4-ab by immunoblot. Lambert-Eaton myastenic syndrome (LEMS) was present in 10 of 23 patients with electrophysiological studies. At least one antibody was detected in 72% of patients. The individual frequencies were: 49% SOX1-ab, 44% VGCC-ab, 31% Hu-ab, and 13% ZIC4-ab. SOX1-ab occurred in 76% of patients with VGCC-ab and 27% of those without VGCC-ab (p = 0.0036). SOX1-ab were not found in 39 patients with sporadic late-onset cerebellar ataxia, 23 with cerebellar ataxia and glutamic acid decarboxylase antibodies, and 73 with PCD and cancer types other than SCLC (31 without onconeural antibodies, 25 with Yo-ab , 17 with Tr-ab). Five patients (13%) had antibodies against unknown neuronal cell surface antigens but none of them improved with immunotherapy. One serum immunoreacted against the axon initial segment of neurons and another serum against ELKS1, a protein highly expressed in the cerebellum that interacts with the beta4-subunit of the VGCC. In conclusion, 72% of patients with PCD and SCLC had one or more antibodies that indicate the presence of this tumor. In these patients, VGCC-ab and SOX1-ab occur tightly associated. SOX1-ab are predictors of SCLC in ataxia patients with a specificity of 100% and sensitivity of 49%. Unlike limbic encephalitis with SCLC, antibodies to cell surface antigens other than VGCC-ab, are infrequent and do not predict response to treatment.

title: Voltage-gated calcium channels.
abstract: Voltage-gated calcium (Ca(2+)) channels are key transducers of membrane potential changes into intracellular Ca(2+) transients that initiate many physiological events. There are ten members of the voltage-gated Ca(2+) channel family in mammals, and they serve distinct roles in cellular signal transduction. The Ca(V)1 subfamily initiates contraction, secretion, regulation of gene expression, integration of synaptic input in neurons, and synaptic transmission at ribbon synapses in specialized sensory cells. The Ca(V)2 subfamily is primarily responsible for initiation of synaptic transmission at fast synapses. The Ca(V)3 subfamily is important for repetitive firing of action potentials in rhythmically firing cells such as cardiac myocytes and thalamic neurons. This article presents the molecular relationships and physiological functions of these Ca(2+) channel proteins and provides information on their molecular, genetic, physiological, and pharmacological properties.

title: Calcium channels in excitable cell membranes.
abstract: The existence of calcium permeability in excitable cells has been appreciated for 30 years (3 I)-almost as long as we have known about voltage-depend­ ent permeabilities to sodium and potassium (46, 47). Yet, to this day, our understanding of Ca channels has lagged far behind our knowledge of Na or K channels. This situation is ironic because Ca channels are widely distributed and rival their better-characterized counterparts in diversity of biological function (42). Ca channels play a crucial role in coupling mem­ brane excitation to cellular responses such as secretion or contraction. They are primarily responsible for some specialized but very interesting forms of excitability-e.g. in the nodal regions of the heart (14, 76), the cilia of Paramecium (11, 12), or the dendrites (64) or growth cones (6) of certain neurons. Unlike Na channels, Ca channels are often modulated by  mones and neurotransmitters. For many years, biophysical or biochemical analysis of Ca channels has been seriously hampered by experimental problems (e.g. 42, 81). No prepa­ ration has been as suitable and no drug as specific for Ca channels as the squid axon and tetrodotoxin are for Na channels. But the state of the art has improved recently with the development of powerful methods for recording Ca channel activity and of blocking drugs that may interact with Ca channels in a potent and specific manner. We now know that Ca channels are pores, capable of transferring millions of permeant ions per second, whose voltage-dependent properties clearly distinguish them from pumps or exchange mechanisms described elsewhere in this volume. There is growing appreciation that Ca channels can be

title: Antibodies against the calcium channel β‐subunit in Lambert‐Eaton myasthenic syndrome
abstract: The sera of patients with Lambert-Eaton myasthenic syndrome (LEMS) contain autoantibodies against several extracellular and intracellular components of the voltage-gated calcium channel (VGCC)/synaptic vesicle release complex. An example of the latter are anti-β-subunit antibodies (anti-MysB antibodies). We constructed a full-length cDNA clone of a human VGCC β-subunit to produce purified β-subunit fusion protein (MysB protein). Using this protein, we demonstrated that anti-β-subunit antibodies are present in the sera of 23% of LEMS patients and only, in low titer, in 2% of small cell lung cancer patients without LEMS. The presence of anti-β-subunit antibodies was closely associated with high titers of P/Q- and N-type VGCC antibodies. Immunization of rats with the purified MysB protein induced high antibody titers, but no signs of neurologic dysfunction were found. We conclude that anti-β-subunit antibodies are not likely to interfere with ion channel function, but their presence could explain the cross-reactivity of LEMS sera with several subtypes of VGCCs and the lack of correlation between anti-VGCC antibody titer and clinical severity of disease.

title: The epidemiology of myasthenia gravis, Lambert-Eaton myasthenic syndrome and their associated tumours in the northern part of the province of South Holland
abstract: We studied the epidemiology of myasthenia gravis (MG) and the Lambert-Eaton myasthenic syndrome (LEMS), and their association with small cell lung carcinoma (SCLC) and thymoma, in a well defined region of the Netherlands. Available data on all the patients with MG, LEMS, thymoma or SCLC living between 1 January 1990 and 31 December 1999 in the northern region of South Holland, with a population of 1.7 million inhabitants, were evaluated. A total of 202 patients with MG (20 with thymoma) and ten patients with LEMS (seven with SCLC) were identified. LEMS was 46 times less prevalent (2.32 × 10−6) than MG (106.1 × 10−6), whereas the annual incidence rate of LEMS was 14 times lower (0.48 × 10−6) than of MG (6.48 × 10−6), reflecting the poor survival of LEMS patients with SCLC. SCLC was diagnosed in 1593 patients, seven (0.44 %) of whom developed LEMS. Mean age at diagnosis of SCLC was significantly lower in SCLC patients with LEMS (p = 0.006). A thymoma was diagnosed in 32 patients, of whom the ten patients with MG (31 %) had a younger age at diagnosis of thymoma than the patients without MG (p = 0.27). This study confirms the increasing prevalence of MG over the last few decades as reported by others, and underscores the relative rarity of LEMS. The frequency of LEMS in our patients with SCLC was lower than reported in previous studies. In patients with a SCLC or thymoma, the tumour was diagnosed at younger age in those who had the associated myasthenic syndrome.

title: Clinical Dutch-English Lambert-Eaton Myasthenic syndrome (LEMS) tumor association prediction score accurately predicts small-cell lung cancer in the LEMS.
abstract: Approximately one half of patients with Lambert-Eaton myasthenic syndrome (LEMS) have small-cell lung carcinomas (SCLC), aggressive tumors with poor prognosis. In view of its profound impact on therapy and survival, we developed and validated a score to identify the presence of SCLC early in the course of LEMS.



We derived a prediction score for SCLC in LEMS in a nationwide cohort of 107 Dutch patients, and validated it in a similar cohort of 112 British patients. A Dutch-English LEMS Tumor Association Prediction (DELTA-P) score was developed based on multivariate logistic regression.



Age at onset, smoking behavior, weight loss, Karnofsky performance status, bulbar involvement, male sexual impotence, and the presence of Sry-like high-mobility group box protein 1 serum antibodies were independent predictors for SCLC in LEMS. A DELTA-P score was derived allocating 1 point for the presence of each of the following items at or within 3 months from onset: age at onset ≥ 50 years, smoking at diagnosis, weight loss ≥ 5%, bulbar involvement, erectile dysfunction, and Karnofsky performance status lower than 70. The area under the curve of the receiver operating curve was 94.4% in the derivation cohort and 94.6% in the validation set. A DELTA-P score of 0 or 1 corresponded to a 0% to 2.6% chance of SCLC, whereas scores of 4, 5, and 6 corresponded to chances of SCLC of 93.5%, 96.6%, and 100%, respectively.



The simple clinical DELTA-P score discriminated patients with LEMS with and without SCLC with high accuracy early in the course of LEMS.

title: Differences in clinical features between the Lambert-Eaton myasthenic syndrome with and without cancer: an analysis of 227 published cases
abstract: To compare the clinical features of patients with the Lambert-Eaton myasthenic syndrome (LEMS) associated with carcinoma, with patients having LEMS but no cancer, reports on LEMS patients were analyzed systematically. 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 anaesthesia (P<0.05). This analysis shows significant differences between CD and NCD cases of LEMS. The male predominance and higher age at onset in patients with a tumor probably reflects the characteristics of patients with small cell lung cancer. The high frequency of additional immunological disorders in patients without malignancy, together with the younger age at onset suggests a similar etiology as other non-paraneoplastic autoimmune diseases.

title: Antibodies to recombinant synaptotagmin and calcium channel subtypes in Lambert-Eaton myasthenic syndrome
abstract: Several proteins have been postulated as possible targets of immune attack in Lambert-Eaton myasthenic syndrome (LEMS). Heterogeneity of autoantibodies in sera from 20 LEMS patients was studied by comparing their reactivity to synaptotagmin, a synaptic vesicle protein, and voltage-gated calcium channels (VGCCs). Six patients' sera (1 with small cell lung carcinoma (SCLC)) contained antibodies specifically recognizing the recombinant synaptotagmin on immunoblots. Thirteen (11 with SCLC) and 16 (11 with SCLC and 1 with poorly differentiated cell carcinoma in the lung) patients' sera immunoprecipitated omega-conotoxin GVIA-labeled N-type and omega-conotoxin MVIIC-labeled Q-type VGCCs, respectively. Three of 6 synaptotagmin-positive sera had cross-reactivity with N and/or Q subtypes of VGCC; the remaining 3 showed no cross-reactivity with VGCCs. Results indicate that LEMS sera are heterogeneous in the spectrum of containing antibodies, and suggest that this heterogeneity reflects the immune response to various synaptic proteins including not only multiple VGCCs but also synaptosecretory complex proteins.

title: Recombinant calcium channel is recognized by Lambert–Eaton myasthenic syndrome antibodies
abstract: The authors studied sera from 36 patients with Lambert–Eaton myasthenic syndrome (LEMS) by immunoblots using the recombinant protein derived from the DNA sequence encoding for the domain III S5-S6 linker of the P/Q-type voltage-gated calcium channel α1 subunit. The results of 18 patients were positive for antibodies to this recombinant protein. The results of 2 of 10 patients with lung cancer without LEMS were also positive.

title: Lambert-Eaton Myasthenic Syndrome; Pathogenesis, Diagnosis, and Therapy
abstract: Lambert-Eaton Myasthenic Syndrome (LEMS) is a rare disease with a well-characterized pathogenesis. In 50% of the patients, LEMS is a paraneoplastic manifestation and caused by a small cell lung carcinoma (SCLC). Both LEMS patients with SCLC and those without this tumour have in 85% of cases pathogenetic antibodies of very high LEMS specificity against voltage-gated calcium channels (VGCCs) in the cell membrane of the presynaptic motor nerve terminal. Better understanding of LEMS pathogenesis has lead to targeted symptomatic therapy aimed at the neuromuscular junction and to semispecific immuno-suppression. For SCLC LEMS, tumour therapy is essential.

title: Lambert–Eaton myasthenic syndrome differential reactivity of tumor versus non-tumor patients to subunits of the voltage-gated calcium channel
abstract: Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease in which the transmission across the neuromuscular junction is disturbed by autoantibodies directed against the presynaptic P/Q-type voltage-gated calcium channels (VGCC). LEMS is paraneoplastic (T-LEMS) in about 60% of patients mostly associated with a small cellular lung carcinoma (SCLC), but occurs spontaneously without a tumor in 40% (NT-LEMS). In most cases neurologic symptoms appear before tumor diagnosis, but there is as yet no clear specific serologic marker to distinguish between NT- and T-LEMS.



To see whether antibodies from patients with NT- and T-LEMS differentially recognize antigenic sites of the alpha 1A subunit of P/Q-type VGCC, we studied serum samples from 22 T-LEMS and 24 NT-LEMS patients. Sera reactivity was tested by Western blot analysis to recombinant proteins corresponding to the extracellular S5-S6 linker region of three out of four domains forming the alpha 1 subunit of P/Q-type VGCC.



Sera from 9/24 (37,5%) NT-LEMS patients, but only 1/22 (4,6%) T-LEMS patients recognized domain IV (p=0,011). Seroreactivity to domains I and III was similar for NT-LEMS and T-LEMS patients (domain I: 8%/14%; domain III: 46%/41%, not significant).



These data suggest that an antibody response to domain IV is more common in LEMS without tumor than in paraneoplastic LEMS. This may have implications for diagnostic workup in LEMS patients without previously established diagnosis of a tumor. Additionally this could point towards a differential autoimmune pathogenesis between T-LEMS and NT-LEMS.

title: Current therapy for Lambert–Eaton myasthenic syndrome: development of 3,4-diaminopyridine phosphate salt as first-line symptomatic treatment
abstract: Lambert–Eaton myasthenic syndrome (LEMS) is a rare pre-synaptic auto-immune disorder of neuromuscular transmission that is characterised by proximal muscle weakness, depressed tendon reflexes and autonomic dysfunction. This review summarises the clinical symptoms, aetiology, diagnosis and treatment options for LEMS. Focus is placed on symptomatic treatment with the potassium channel blocker 3,4-diaminopyridine (3,4-DAP).  English-language publications were searched in MEDLINE and EMBASE to retrieve relevant literature on LEMS. The data submitted to obtain regulatory approval of 3,4-DAP phosphate by the European Medicines Agency (EMA) were also used.  LEMS is a rare disease with few treatment options which are generally categorised as anti-tumour, immunomodulating or immunosuppressing, and symptomatic treatments. Anti-tumour treatment is recommended for patients with the paraneoplastic form of LEMS. While several immunomodulating or immunosuppressing treatments have been identified, these treatments should be initiated when symptomatic treatments are inadequate. As expected, due to the rarity of the disease, few reports of randomised controlled trials (RCTs) exist. Seven RCTs have been conducted to evaluate treatment of patients with LEMS. One RCT evaluated immunomodulating treatment with intravenous immunoglobulin (ivIg), while six evaluated symptomatic treatment with the potassium channel blocker 3,4-DAP. Improvements in LEMS symptoms after ivIg treatment were observed, leading to the recommendation for treatment in patients when symptomatic treatment does not provide satisfactory improvement. Potassium channel blockers evaluated for the treatment of LEMS include guanidine, 4-aminopyridine (4-AP) and 3,4-DAP. However, only 3,4-DAP has been evaluated in RCTs. Results of these RCTs demonstrated that treatment with 3,4-DAP is efficacious in treatment of LEMS and has an acceptable tolerability profile. Hence, 3,4-DAP has been recommended as first-line symptomatic treatment for LEMS by the European Federation of Neurological Societies. While 3,4-DAP base has only been available via named-patient programmes, requiring ad hoc preparations in compounding pharmacies, tablets containing 3,4-DAP phosphate salt, equivalent to 10 mg base, have become available. This formulation has obtained the orphan medicinal product status both in the European Union and in the United States of America, and has received marketing authorisation in Europe as Firdapse. These tablets have been shown to be essentially bioequivalent with the base preparation.  The results of this review show that anti-tumour treatment is recommended for patients with the paraneoplastic form of LEMS and that one RCT has shown that immunomodulating treatments should be initiated when symptomatic treatments do not provide satisfactory results. A number of RCTs have shown that 3,4-DAP is effective in symptomatic treatment of patients with LEMS and has been recommended as first-line symptomatic treatment of patients with LEMS. The 3,4-DAP phosphate salt formulation was shown to be safe and effective in the treatment of LEMS with a positive benefit:risk ratio.

title: SOX antibodies in small-cell lung cancer and Lambert-Eaton myasthenic syndrome: frequency and relation with survival.
abstract: SOX1 antibodies are common in small-cell lung carcinoma (SCLC) with and without paraneoplastic syndrome (PNS) and can serve as serological tumor marker. Addition of other antibodies might improve its diagnostic power. We validated an enzyme-linked immunosorbent assay (ELISA) to assess the diagnostic value of serum antibodies in SCLC and Lambert-Eaton myasthenic syndrome (LEMS). Clinical outcome with respect to SOX antibodies was evaluated, as the SOX-related antitumor immune response might help to control the tumor growth.



We used recombinant SOX1, SOX2, SOX3, SOX21, HuC, HuD, or HelN1 proteins in an ELISA to titrate serum samples and validated the assay by western blot. We tested 136 consecutive SCLC patients, 86 LEMS patients (43 with SCLC), 14 patients with SCLC and PNS (paraneoplastic cerebellar degeneration or Hu syndrome), 62 polyneuropathy patients, and 18 healthy controls.



Our ELISA was equally reliable as western blot. Forty-three percent of SCLC patients and 67% of SCLC-LEMS patients had antibodies to one of the SOX or Hu proteins. SOX antibodies had a sensitivity of 67% and a specificity of 95% to discriminate between LEMS with SCLC and nontumor LEMS. No difference in survival was observed between SOX positive and SOX negative SCLC patients.



SOX antibodies are specific serological markers for SCLC. Our assay is suitable for high throughput screening, detecting 43% of SCLC. SOX antibodies have diagnostic value in discriminating SCLC-LEMS from nontumor LEMS, but have no relation to survival in patients with SCLC.

title: Incidence of serum anti-P/Q-type and anti-N-type calcium channel autoantibodies in the Lambert-Eaton myasthenic syndrome
abstract: The Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease in which autoantibodies are directed against voltage-gated calcium channels (VGCCs) at presynaptic nerve terminals. We first demonstrated the presence of P/Q-type and N-type VGCCs in digitonin extracts prepared from human and rabbit cerebellum using the specific ligands 125I-omega-conotoxin MVIIC (125I-omega-CmTx) and 125I-omega-conotoxin GVIA (125I-omega-CgTx), respectively. We then tested sera from 72 LEMS patients' 25 with proven small cell lung cancer (SCLC) and 66 healthy or other neurological, SCLC or autoimmune disease controls in an immunoprecipitation assay using 125I-omega-CmTx-labelled (P/Q-type) VGCCs in human cerebellar extract. Sixty-six of 72 LEMS serum samples (91.7%) were positive for the presence of VGCC antibodies, as defined as a titre greater than 3 standard deviations above the mean for the healthy controls (n = 22). Rabbit cerebellar extract as antigen gave similar results (r = 0.94, P < 0.001, n = 30). By contrast, only 24/72 (33%) LEMS sera were positive in the assay for anti-N-type VGCC antibodies using 125I-omega-CgTx. All these 24 were also positive in the 125I-omega-CmTx assay. All healthy and disease control sera were negative in both assays. The anti-P/Q-type VGCC antibody titres did not correlate with an electrophysiological index of disease severity across individuals; however, longitudinal studies in a LEMS patient with SCLC receiving chemotherapy, and in a non-SCLC LEMS patient receiving immunosuppressive therapy showed an inverse relation between antibody titre and disease severity. These results support the view that anti-P/Q-type VGCC antibodies are implicated in the motor disorder in LEMS, and show that the omega-CmTx radioimmunoassay is a highly specific and sensitive means of detecting them.

title: Synaptotagmin can cause an immune‐mediated model of Lambert‐Eaton myasthenic syndrome in rats
abstract: The possible antigenicity of synaptotagmin, a synaptic vesicle protein acting as a cooperative calcium (Ca2+) receptor in exocytosis, was tested to determine whether it is involved in the induction of Lambert‐Eaton myasthenic syndrome in which antibodies against voltage‐dependent Ca2+ channels or related molecules play a pathogenic role. Repeated injections to Lewis rats with peptides of synaptotagmin residues 20 through 53 or 1 through 30 that are presumably exposed at the nerve terminal surface during exocytosis induced corresponding antipeptide antibodies; on immunoblots, antibodies recognized synaptotagmin that was expressed in the clonal cells. Electrophysiologically, the peptide (residues 20–53)‐immunized rats showed (1) reduced acetylcholine quantal content of end‐plate potential, (2) an increase in quantal content at high extracellular Ca2+ concentration, and (3) early facilitation followed by less marked depression of end‐plate potential amplitude at a tetanic rate of repetitive nerve stimulation. Findings are similar to those in human Lambert‐Eaton myasthenic syndrome and passively transferred Lambert‐Eaton myasthenic syndrome in mice, and thus suggest that antibody to a synaptotagmin–voltage‐dependent Ca2+ channel complex may be involved in the pathogenesis of Lambert‐Eaton myasthenic syndrome. The peptide (residues 1–30)‐immunized rats showed no electrophysiological abnormality.

title: Role of the conserved WHXL motif in the C terminus of synaptotagmin in synaptic vesicle docking.
abstract: Synaptotagmin (Syt) I, an abundant synaptic vesicle protein, consists of one transmembrane region, two C2 domains, and a short C terminus. This protein is essential for both synaptic vesicle exocytosis and endocytosis via its C2 domains. Although the short C terminus is highly conserved among the Syt family and across species, little is known about the exact role of the conserved C terminus of Syt I. In this paper, we report a function of the Syt I C terminus in synaptic vesicle docking at the active zones. Presynaptic injection of a peptide corresponding to the C-terminal 21 amino acids of Syt I (named Syt-C) into the squid giant synapse blocked synaptic transmission without affecting the presynaptic action potential or the presynaptic Ca(2+) currents. The same procedure repeated with a mutant C-terminal peptide (Syt-CM) had no effect on synaptic transmission. Repetitive presynaptic stimulation with Syt-C produced a rapid decrease in the amplitude of the postsynaptic potentials as the synaptic block progressed, indicating that the peptide interferes with the docking step rather than the fusion step of synaptic vesicles. Electron microscopy of the synapses injected with the Syt-C peptide showed a marked decrease in the number of docked synaptic vesicles at the active zones, as compared with controls. These results indicate that Syt I is a multifunctional protein that is involved in at least three steps of synaptic vesicle cycle: docking, fusion, and reuptake of synaptic vesicles.

title: Regulatory T cells in paraneoplastic neurological syndromes
abstract: Focusing on CD4(+)CD25(+) regulatory T lymphocytes (T(reg)), we studied the gene expression of T(reg) functional molecules in peripheral blood lymphocytes of patients with paraneoplastic neurological syndrome (PNS), including Lambert-Eaton myasthenic syndrome (LEMS) with small cell lung carcinoma (SCLC) and anti-Hu- or anti-Yo-antibody-positive PNS. T(reg)-rich subsets were sorted from the patients' peripheral blood mononuclear cells, and the mRNA expression levels of their functional genes were measured. The expression levels of FOXP3, TGF-beta and CTLA4 mRNA in T(reg)-rich subsets of PNS patients were down-regulated compared with that of SCLC patients without PNS. These results suggest that T(reg) dysfunction plays a role in PNS development.

title: HLA class I and II in Lambert-Eaton myasthenic syndrome without associated tumor.
abstract: Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder, in which antibodies against voltage-gated calcium channels located at nerve terminals cause muscle weakness and autonomic dysfunction. In approximately half of the patients the autoimmune process is initiated by a tumor. In the other half of patients no tumor is found and the etiology is unknown. The aims of this study were to investigate the strength of HLA-associations with nontumor LEMS (NT-LEMS) and to study the relation of HLA-haplotypes with age at onset of LEMS and other clinical features. Therefore, typing of HLA class I and II was performed in 19 patients with NT-LEMS, who were clinically evaluated. NT-LEMS was significantly associated with alleles of both HLA-class I (i.e. HLA-B8) as well as -class II (i.e. HLA-DR3 and -DQ2). HLA-B8+ patients had significantly younger age at onset of LEMS and tended to be female. This study shows that HLA-class I haplotype is associated with a distinct phenotype in NT-LEMS.

title: Monozygous twins with neuromuscular transmission defects at opposite sides of the motor endplate
abstract: Disorders affecting the postsynaptic side of the neuromuscular junction include autoimmune myasthenia gravis (MG) as well as some of the congenital myasthenic syndromes (CMS). Lambert‐Eaton myasthenic syndrome (LEMS) is an acquired autoimmune neuromuscular disorder in which autoantibodies are directed against the presynaptic calcium channels. Here we describe two monozygous twin brothers: case 1 was diagnosed with an indeterminate form of acquired postsynaptic neuromuscular junction defect at age 32 and case 2 with LEMS at age 47. Case 1 presented clinically with mild generalized myasthenic weakness, neurophysiological examination revealed disturbed neuromuscular transmission along with probable myositis and serum analysis regarding antibodies against the acetylcholine receptor and muscle‐specific tyrosine kinase was negative. Case 2 presented with proximal muscle fatigue accompanied by areflexia at rest and antibodies against the P/Q‐type voltage‐gated calcium channels were present. Neurophysiologically, case 2 had reduced baseline compound motor action potential amplitudes on neurography, decrement on low‐frequency repetitive nerve stimulation (RNS) and pathological increment on high frequency RNS. To our knowledge this is the first case report of its kind and adds an intriguing contrast to the more common diagnosis of CMS in monozygous twins.

title: The Lambert–Eaton myasthenic syndrome 1988–2008: A clinical picture in 97 patients
abstract: Neuromuscular symptoms in patients with Lambert-Eaton myasthenic syndrome (LEMS) and a small cell lung cancer (SCLC) develop more rapidly than in LEMS patients without a SCLC. We studied how this clinical information, which is readily available at the first consultation, can be used to predict the presence of SCLC.



In our study we included 52 LEMS patients with SCLC and 45 non-tumor patients (NT-LEMS). We interviewed patients using a structured checklist and reviewed their clinical records. We compared frequency and onset of symptoms during the course of LEMS.



In the first six months, over half the SCLC-LEMS patients had developed seven separate symptoms, while NT-LEMS patients developed only two symptoms. Proximal leg weakness and dry mouth were early symptoms in both groups. Rapid involvement of proximal arm muscles (p=0.0001), distal arm muscles (p=0.0037), distal leg muscles (p=0.0002), dysartria (p=0.0091) and the presence of erectile dysfunction (p=0.007) were found significantly more often in SCLC-LEMS patients in both cohorts. Cerebellar symptoms, although present in 9% of LEMS patients, were almost exclusively related to SCLC-LEMS.



A rapidly progressive course of disease from onset in LEMS patients should raise a high suspicion of SCLC. Special attention should be paid to involvement of upper extremities, involvement of distal arm and distal leg muscles, to erectile dysfunction and probably ataxia in order to discriminate between SCLC-LEMS and NT-LEMS.

title: Managing non-paraneoplastic Lambert–Eaton myasthenic syndrome: Clinical characteristics in 25 German patients
abstract: In about 40% of patients LEMS is not a paraneoplastic phenomenon (NT-LEMS). Several clinical aspects important to these patients remain open, especially the question when a LEMS can definitely be diagnosed as NT-LEMS. Here we describe a series of 25 German NT-LEMS patients regarding their clinical characteristics, duration of symptoms, value of serological markers, paraneoplastic antibodies and FDG-PET/CT. Furthermore, we discuss the current diagnostic criteria of NT-LEMS.

title: SOX1 antibodies are markers of paraneoplastic Lambert–Eaton myasthenic syndrome
abstract: We reported that 43% of patients with Lambert–Eaton myasthenic syndrome (LEMS) and small cell lung cancer (SCLC) had an antibody called anti-glial nuclear antibody (AGNA), defined by the immunoreaction with the nuclei of the Bergmann glia of the cerebellum. This study was undertaken to identify the antigen recognized by AGNA and to confirm the association with paraneoplastic LEMS in a larger series.  We probed a fetal brain cDNA library with AGNA-positive sera. The presence of antibodies against the isolated antigen was detected by immunoblot of phage plaques from two positive clones. We studied 105 patients with LEMS (55 with SCLC), 50 with paraneoplastic neurologic syndromes, SCLC, and Hu antibodies, and 50 with only SCLC.  Probing of the fetal brain expression library with AGNA sera resulted in the isolation of SOX1, a highly immunogenic tumor antigen in SCLC. IgG eluted from SOX1 clones produced the same cerebellar immunoreactivity as of AGNA sera. SOX1 antibodies were present in 64% of patients with LEMS and SCLC but in none of the 50 with idiopathic LEMS (p < 0.0001). Compared with paraneoplastic LEMS, the frequency of SOX1 antibodies was significantly lower in patients with Hu antibodies (32%, p = 0.002) and in those with only SCLC (22%).  SOX1 is the antigen recognized by anti-glial nuclear antibody–positive sera. The detection of SOX1 antibodies in patients with Lambert–Eaton myasthenic syndrome (LEMS) predicts the presence of small cell lung cancer and may be used to follow more closely those LEMS patients with no evidence of cancer at the initial workup.

title: [Lambert-Eaton myastenic syndrome revealing neuroblastoma in 2 children].
abstract: Lambert-Eaton myasthenic syndrome is a paraneoplasic syndrome which can reveal a primitive tumor. Frequently, the first diagnosis is myasthenia gravis. This disease is extremely rare in children. Only 10 cases have been reported in the last 35 years. We report 2 new observations occurring in very young patients, aged 2 and 3 years, with a ganglioneurobastoma as primitive tumor.

title: Associated autoimmune diseases in patients with the Lambert-Eaton myasthenic syndrome and their families
abstract: In view of the clustering of autoimmune diseases (AIDs), we studied the frequency and nature of additional AIDs in patients with the Lambert-Eaton myasthenic syndrome (LEMS) and their family members, in both small cell lung carcinoma (SCLC) related and non-tumour (NT) related cases. Additional AIDs in patients with LEMS were assessed by interviewing the patient and studying the medical record. Family histories up to second-degree family members were established by interviewing patients, controls and family members. Forty-four patients with LEMS were assessed, of whom eighteen (41%) had SCLC. In the NT group seven patients (27%) had an additional AID, in the SCLC group two (11 %) (p=0.20). Thyroid disorder (five patients) and insulin dependent diabetes mellitus (two patients) were the most common AIDs. AIDs were significantly more frequent in families of patients with NT-LEMS (64%) than in control families (27%) (p=0.002), which was not found in SCLC-LEMS (36%, p=0.53). Affected family members were linked to the NT-LEMS patient through the maternal line in all cases. In conclusion, AIDs were more frequently found in LEMS patients without a tumour and their families, which could not be shown for SCLC-LEMS. This suggests that NT-LEMS shares immunogenetic factors with other AIDs. In families of NT-LEMS, a remarkable preponderance of maternal inheritance was seen, as has been reported previously in myasthenia gravis.

title: Practice parameter for repetitive nerve stimulation and single fiber EMG evaluation of adults with suspected myasthenia gravis or Lambert–Eaton myasthenic syndrome: Summary statement
abstract: A retrospective literature review of the electrodiagnosis of myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) through July 1998 was performed for the purpose of generating evidence10 based practice parameters. There were 545 articles identified, of which 13 articles met at least 3 of the 6 criteria set previously by the American Association of Electrodiagnostic Medicine (AAEM). An additional 21 articles were identified from review articles or the references of these first 13 articles leading to a total of 34 articles. Results of studies utilizing repetitive nerve stimulation (RNS) showed that a 10% decrement in amplitude from the first to fourth or fifth intravolley waveform while stimulating at 2 5 Hz is valid for the diagnosis of MG. The degree of increment needed for the diagnosis of LEMS is at least 25% but most accurate when greater than 100%. Abnormal jitter or impulse blocking are the appropriate criteria for diagnosis of neuromuscular junction (NMJ) disorders when using single fiber electromyography (SFEMG). SFEMG is more sensitive than RNS for the diagnosis of disorders of neuromuscular transmission but may be less specific and may not be available. Therefore, RNS remains the preferred initial test for MG and LEMS.

title: Electrophysiological diagnostic criteria of Lambert–Eaton myasthenic syndrome
abstract: Various parameters of the repetitive nerve stimulation (RNS) test of the abductor digiti quinti muscle were analyzed statistically in 34 patients with Lambert–Eaton myasthenic syndrome (LEMS). The sensitivity and specificity of the increments after exercise and after 50‐HZ stimulation for the diagnosis of LEMS were compared with reference values in 40 normal subjects and data from 538 tests in patients with myasthenia gravis (MG). When we used a 100% increment (the “gold standard”) as the normal limit for the postexercise facilitation (PEF) or the high‐rate stimulation (HRS) test, the diagnosis of LEMS was confirmed in 29 (85%) cases. When a 60% increment was used as the normal limit, the diagnosis of LEMS was made in 97% of cases. In MG, a 60% increment was observed in only 4 of 538 cases by HRS and in none by the exercise test. Thus, the use of a 60% increment showed a sensitivity of 97% for the diagnosis of LEMS and a specificity of 99% in excluding MG. A 60% increment in either the PEF or HRS test for the diagnosis of LEMS is a desirable alternative to the 100% increment previously considered to be the gold standard for this diagnosis. Muscle Nerve, 2005

title: The Lambert-Eaton myasthenic syndrome. A review of 50 cases.
abstract: The clinical and electrophysiological features of 50 consecutive patients with the Lambert-Eaton myasthenic syndrome (LEMS) have been analysed. Carcinoma was detected (CD group) in 25, of whom 21 had small cell lung cancer (SCLC). SCLC was evident within 2 yrs of onset of LEMS symptoms in 20/21 cases, and at 3.8 yrs in 1/21. In the cases in whom no carcinoma was detected (NCD group), 14/25 had a history of LEMS greater than 5 yrs. The dominant neurological features were similar in the CD and NCD groups, and consisted of proximal lower limb weakness (100%), depressed tendon reflexes (92%) with posttetanic potentiation (78%), autonomic features, especially dryness of the mouth (74%) and mild/moderate ptosis (54%). The compound evoked muscle action potential amplitude in abductor digiti minimi was below the lower limit of control values in 48/50, and the increment following maximum voluntary contraction above the upper limit of control values in 48/50. Single fibre electromyographic abnormalities were found in 29/29 cases. The analysis indicates that a patient presenting with LEMS has a 62% risk of an underlying SCLC, and that this risk declines sharply after 2 yrs, becoming very low at 4 to 5 yrs. It is argued that in SCLC cases antigenic determinants on tumour cells initiate the autoimmune response, often early in the course of the malignancy, but that the association of LEMS with tumours other than SCLC may be fortuitous. In the latter, and in NCD patients, the initiating factor(s) are unknown.

title: Screening for tumours in paraneoplastic syndromes: report of an EFNS Task Force
abstract: Paraneoplastic neurological syndromes (PNS) almost invariably predate detection of the malignancy. Screening for tumours is important in PNS as the tumour directly affects prognosis and treatment and should be performed as soon as possible.

title: Treatment for Lambert-Eaton myasthenic syndrome.
abstract: Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of neuromuscular transmission. Treatments attempt to overcome the harmful autoimmune process, or improve residual neuromuscular transmission



The objective was to examine the efficacy of treatment in Lambert-Eaton myasthenic syndrome.


SEARCH STRATEGY
We searched the Cochrane Neuromuscular Disease Group Specialized Register (12 October 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (12 October 2010, Issue 4 2010 in the Cochrane Library), MEDLINE (January 1966 to September 2010) and EMBASE (January 1980 to September 2010).



All randomised or quasi-randomised trials of adults and children with a diagnosis of Lambert-Eaton myasthenic syndrome, with or without small-cell lung cancer, receiving any form of pharmacological or physical treatment.



All authors independently assessed studies for inclusion and extracted data. Study authors were contacted for missing information when possible.



Four controlled trials of 3,4-diaminopyridine compared with placebo in a total of 54 participants with Lambert-Eaton myasthenic syndrome were eligible: three cross-over trials and one parallel group. Two were added at this update. One of these trials also assessed pyridostigmine in conjunction with 3,4-diaminopyridine. A further cross-over trial compared intravenous immunoglobulin (IVIg) to placebo in nine participants.Four trials of 3,4-diaminopyridine reported significant improvement in the primary outcome, muscle strength score, or myometric limb measurement for between hours and a week following treatment, and significant improvement in resting compound muscle action potential (CMAP) amplitude following 3,4-diaminopyridine, compared with placebo.A meta-analysis of the primary endpoint showed Quantitative Myasthenia Gravis (QMG) muscle score assessed between three and eight days was likely to improve by a mean of 2.44 points (95% confidence interval 3.6 to 1.22). Meta-analysis of the secondary endpoint CMAP amplitude also showed a mean improvement of 1.36 mV (95% confidence interval 0.99 to 1.72) over the same period. The risk of bias was determined to be low, and quality of evidence moderate to high.A single cross-over trial reported significant improvement in myometric limb strength and non-significant improvement in mean resting CMAP amplitude with IVIg compared to placebo. Clinical improvement lasted for up to eight weeks.



Limited but moderate to high quality evidence from randomised controlled trials showed that over days 3,4-diaminopyridine, or for up to 8 weeks IVIg, improved muscle strength scores and CMAP amplitudes in participants with Lambert-Eaton myasthenic syndrome. There are insufficient data at present to quantify this effect. Other possible treatments have not been tested in randomised controlled trials.

title: Potency of 3,4-diaminopyridine and 4-aminopyridine on mammalian neuromuscular transmission and the effect of pH changes.
abstract: 3,4-Diaminopyridine (3,4-DAP) like 4-aminopyridine (4-AP) greatly increased stimulus-evoked transmitter release, recorded as end-plate potentials, in single fibers of the isolated mouse nerve-hemidiaphragm preparation. 3,4-DAP was 6–7 times more potent in this respect than 4-AP. 3,4-DAP was able to restore, from complete paralysis, neuromuscular transmission in isolated botulinum toxin (type A)-poisoned rat muscles and in this respect also was 6–7 times more potent than 4-AP. Changing the pH of the external solution from 7.4 to 9.0 had no significant effect on nerve-evoked transmitter release. However, both 4-AP and 3,4-DAP, which have pKa values of about 9, were about 3 times more potent in increasing transmitter release at pH 9.0 than at pH 7.4. This was interpreted to mean that the two molecules are more effective in their unionized form and therefore possibly exert their effect on transmitter release at an intracellular site in the nerve terminal. The slope values for the calcium dependence of nerve-evoked transmitter release were similar at pH 7.4 and 9.0 and were not altered by 3,4-DAP or 4-AP. Like 4-AP, 3,4-DAP converted the end-plate potential produced by electronic depolarization of tetrodotoxin-blocked frog nerve terminals into an all-or-none response, implying that the drugs enhance transmitter release by greatly increasing the voltage-dependent calcium conductance of the nerve terminal membrane.

title: Update on treatment options for Lambert–Eaton myasthenic syndrome: focus on use of amifampridine
abstract: In Lambert–Eaton myasthenic syndrome (LEMS), antibodies against presynaptic voltage-gated calcium channels reduce the quantal release of acetylcholine, causing muscle weakness and autonomic dysfunction. More than half of the affected patients have associated small cell lung cancer, and thorough screening for an underlying malignancy is crucial. The mainstay of treatment for LEMS is symptomatic but immunotherapy is needed in more severely affected patients. Symptomatic therapies aim at increasing the concentration of acetylcholine at the muscle endplate. While acetylcholinesterase inhibitors were the first drugs to be used for the amelioration of symptoms, 3,4-diaminopyridine (3,4-DAP, amifampridine) has been shown to be more effective. 3,4-DAP blocks presynaptic potassium channels, thereby prolonging the action potential and increasing presynaptic calcium concentrations. This then results in increased quantal release of acetylcholine. The efficacy of 3,4-DAP for increasing muscle strength and resting compound muscle action potentials has been demonstrated by four placebo-controlled trials. Side effects are usually mild, and the most frequently reported are paresthesias. The most common serious adverse events are epileptic seizures. 3,4-DAP is currently the treatment of choice in patients with Lambert–Eaton myasthenic syndrome.

title: A randomized trial of 3,4-diaminopyridine in Lambert-Eaton myasthenic syndrome
abstract: The authors report the results of a prospective, placebo-controlled, randomized study to evaluate the effectiveness of 3,4-diaminopyridine (DAP) in patients with Lambert-Eaton myasthenic syndrome (LEMS) and to determine the acute and long-term side effects of DAP.  Twenty-six patients with LEMS completed a two-arm parallel treatment protocol in which DAP, 20 mg three times daily, or placebo was given blindly for 6 days, and a quantitative examination of muscle strength (the quantitative myasthenia gravis [QMG] score) was used as the primary measure of efficacy. After the blinded study, patients were given open-label DAP and monitored for side effects as long as there was symptomatic improvement.  Twelve patients took DAP, and 14 took placebo. There was no difference in the age of LEMS onset, gender distribution, incidence of lung cancer, or baseline muscle strength between the patients who were randomly assigned to receive placebo and those randomly assigned to DAP. Statistical analysis using the Wilcoxon’s rank sum test demonstrated that patients who received DAP had a significantly greater improvement in the QMG score and in the summated amplitude of compound muscle action potentials recorded from three sentinel limb muscles. All but one LEMS patient had significant symptomatic improvement from subsequent open-label DAP. Side effects of DAP were negligible, consisting of perioral and digital paresthesia. Laboratory measurements demonstrated no evidence of toxicity affecting liver, renal, hematologic, endocrinologic, encephalographic, or electrocardiologic function acutely or after 6 months of open-label DAP.  This study corroborates previous studies and many years of clinical experience showing that DAP is an effective and safe treatment for LEMS.

title: Guidelines for treatment of autoimmune neuromuscular transmission disorders
abstract: Important progress has been made in our understanding of the autoimmune neuromuscular transmission (NMT) disorders; myasthenia gravis (MG), Lambert–Eaton myasthenic syndrome (LEMS) and neuromyotonia (Isaacs’ syndrome).

title: EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurological diseases
abstract: Despite high‐dose intravenous immunoglobulin (IVIG) is widely used in treatment of a number of immune‐mediated neurological diseases, the consensus on its optimal use is insufficient. To define the evidence‐based optimal use of IVIG in neurology, the recent papers of high relevance were reviewed and consensus recommendations are given according to EFNS guidance regulations. The efficacy of IVIG has been proven in Guillain‐Barré syndrome (level A), chronic inflammatory demyelinating polyradiculoneuropathy (level A), multifocal mononeuropathy (level A), acute exacerbations of myasthenia gravis (MG) and short‐term treatment of severe MG (level A recommendation), and some paraneoplastic neuropathies (level B). IVIG is recommended as a second‐line treatment in combination with prednisone in dermatomyositis (level B) and treatment option in polymyositis (level C). IVIG should be considered as a second or third‐line therapy in relapsing–remitting multiple sclerosis, if conventional immunomodulatory therapies are not tolerated (level B), and in relapses during pregnancy or post‐partum period (good clinical practice point). IVIG seems to have a favourable effect also in paraneoplastic neurological diseases (level A), stiff‐person syndrome (level A), some acute‐demyelinating diseases and childhood refractory epilepsy (good practice point).

title: Transient neonatal Lambert-Eaton syndrome
abstract: JO N 2988 immune disease of the neuromuscular synapse mediated by serum IgG against voltage-gated calcium channel antibodies (anti-VGCC AB). The disorder is 60 % paraneoplastic (small-cell lung cancer) (PLEMS); the remainder presents no cancer-association (NP-LEMS) [7–9]. Placental transfer of antiVGCC antibodies in LEMS similarly resulting in transient neonatal LEMS has not been noted previously. We report on the pregnancy and premature delivery in a 34 year old (I gravida, I para) with NP-LEMS. After diagnosis of LEMS at 30 years, treatment was initiated, initially with pyridostigmine without success, consecutively with 3,4diaminopyridine (100 mg/d) with significant clinical improvement and anti-VGCC AB titres between 453.4–566.4 pmol/L (normal range < 30 pmol/L). During pregnancy the patient remained clinically stable under unmodified pharmacotherapy (anti-VGCC AB titres , while the foetus presented mild intrauterine growth retardation. In the 24th week of gestation imminent premature labour called for tocolysis, uneventfully performed with magnesium 3 × 200 mg and glyceroltrinitrate 10 mg. In the 36th week of gestation caesarean section was performed because of premature labour and pathologic CTG. Ulrike Reuner Gabriele Kamin Georgia Ramantani Heinz Reichmann Jürgen Dinger

title: Lambert-Eaton myasthenic syndrome.
abstract: The Lambert-Eaton Myasthenic Syndrome (LEMS) is characterised by proximal muscle weakness initially affecting gait, autonomic symptoms (dry mouth, constipation, erectile failure), augmentation of strength during initial voluntary activation, and depressed tendon reflexes with post-tetanic potentiation. The disorder is paraneoplastic (small cell lung cancer) in about 60p. cent (P-LEMS); no cancer is associated in the remainder (NP-LEMS). LEMS affects all races. NP-LEMS can occur in childhood as well as adult life; P-LEMS is unusual at<30 Years. The weakness results from a reduction in the quantal release of acetylcholine from motor nerve terminals, caused by autoantibodies to P/Q-type voltage-gated calcium channels (VGCCs) that are provoked by tumour VGCCs in P-LEMS; the stimulus in NP-LEMS is not known. These antibodies may be implicated in the rarely associated cerebellar degeneration. The diagnosis can be confirmed by detecting the specific antibody in a radioimmunoprecipitation assay, and by finding a reduced compound muscle action potential amplitude that increases by>100p. cent following maximum voluntary activation. Most patients benefit from 3,4-diaminopyridine; pyridostigmine is less effective. Specific tumour therapy in P-LEMS will often ameliorate the neurological disorder. In those with severe weakness, IVIg or plasmapheresis confers short-term benefits. Prednisone alone or combined with azathioprine or cyclosporin can achieve long-term control of the disorder.

title: HLA and smoking in prediction and prognosis of small cell lung cancer in autoimmune Lambert–Eaton myasthenic syndrome
abstract: Patients with small cell lung cancer (SCLC) survive longer if they have the antibody-mediated Lambert-Eaton myasthenic syndrome (LEMS), making this autoimmune disorder a prototype disease for studying cancer immunosurveillance. Patients with nontumor LEMS (NT-LEMS) never develop SCLC but are otherwise indistinguishable clinically. Therefore, we have compared immunogenetic factors in SCLC-LEMS and NT-LEMS and studied their role in the pathogenesis of LEMS and survival from SCLC. In 48 British and 29 Dutch Caucasian LEMS patients, we studied clinical symptoms, antibody titers, HLA types and alleles at six nearby located microsatellite loci. Highly significant associations were found in NT-LEMS, which appeared strongest with HLA-B8, but also involved HLA-DQ2, -DR3 and six flanking microsatellite alleles. LEMS patients were not different from controls. Smoking was a strong predictor of SCLC. In contrast, HLA-B8 positivity correlated with a decreased risk of SCLC even among the smokers. Moreover, in SCLC-LEMS patients, HLA-B8 positivity correlated with prolonged survival after LEMS onset. We propose that two distinct immunopathogenetic routes can lead to one clinically and serologically indistinguishable autoimmune myasthenic syndrome. HLA-DR3-B8 is strongly associated with LEMS in nontumor patients only. In other LEMS patients, SCLC apparently provides a powerful autoimmunogenic stimulus that overrides HLA restrictions in breaking tolerance to calcium channels. Moreover, negativity for HLA-B8 combined with smoking behavior points more strongly to an underlying SCLC and predicts a worse prognosis in SCLC-LEMS patients.

title: Neuro-ophthalmologic manifestations of paraneoplastic syndromes.
abstract: Paraneoplastic syndromes with neuro-ophthalmologic manifestations may involve the central nervous system, cranial nerves, neuromuscular junction, optic nerve, uvea, or retina. Most of these disorders are related to immunologic mechanisms presumably triggered by the neoplastic expression of neuronal proteins. Accurate recognition is essential to appropriate management.

title: Paraneoplastic syndromes of the CNS
abstract: Major advances in the management of paraneoplastic neurologic disorders (PND) include the detection of new antineuronal antibodies, the improved characterisation of known syndromes, the discovery of new syndromes, and the use of CT and PET to reveal the associated tumours at an early stage. In addition, the definition of useful clinical criteria has facilitated the early recognition and treatment of these disorders. In this article, we review some classic concepts about PND and recent clinical and immunological developments, focusing on paraneoplastic cerebellar degeneration, opsoclonus-myoclonus, and encephalitides affecting the limbic system.

title: Reduction of P/Q‐type calcium channels in the postmortem cerebellum of paraneoplastic cerebellar degeneration with Lambert‐Eaton myasthenic syndrome
abstract: 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‐ω‐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 ± 7.0fmol/mg, n = 3), compared with the controls (297.8 ± 38.9fmol/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 125I‐ω‐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.

title: Intrathecal injection of P/Q type voltage-gated calcium channel antibodies from paraneoplastic cerebellar degeneration cause ataxia in mice
abstract: The role of antibodies against the P/Q type voltage-gated calcium channels (VGCC-ab) in the pathogenesis of paraneoplastic cerebellar degeneration (PCD) and lung cancer is unclear. We evaluated in mice the effect of intrathecal injection of IgG purified from serum of a patient with both PCD and Lambert-Eaton myasthenic syndrome (LEMS), and from another patient with isolated LEMS. Mice injected with PCD/LEMS IgG developed marked, reversible ataxia compared with those injected with LEMS or control IgG. These findings suggest that P/Q-type VGCC-ab may play a role in the pathogenesis of ataxia in patients with PCD and SCLC.

title: Cerebellar hypermetabolism in paraneoplastic cerebellar degeneration
abstract: A 51 year old man with paraneoplastic cerebellar degeneration from gastric adenocarcinoma showed cerebellar hypermetabolism and increased perfusion on brain FDG-PET scan and SPECT during the acute stage of his illness. The patient underwent subtotal gastrectomy. The intensity of the hypermetabolism had decreased markedly on follow-up FDG-PET 3 months later following two cycles of chemotherapy. We suggest that the cerebellar hypermetabolism may have been due to an acute inflammatory process associated with an immunological reaction.

title: Antineuronal antibodies in sporadic late-onset cerebellar ataxia
abstract: Sporadic late-onset cerebellar ataxia of unknown cause is considered a neurodegenerative disorder whose underlying mechanisms are still unknown. To identify antineuronal autoantibodies, immunohistochemical and immunoblotting techniques were performed in 67 patients with sporadic cerebellar degeneration of unknown cause. Elevated P/Q-type voltage-gated calcium channel (VGCC)-specific antibodies were found in eight patients (11.9%). There was no hint of a paraneoplastic disorder in any of the patients. The present findings suggest an autoimmune contribution to the pathophysiology of a subgroup of sporadic late-onset cerebellar ataxia.

title: Cerebellar ataxia in non-paraneoplastic Lambert–Eaton myasthenic syndrome
abstract: Lambert-Eaton myasthenic syndrome (LEMS) is an immune-mediated disorder of the neuromuscular junction that rarely is associated with cerebellar ataxia (CA). We describe two patients with non-paraneoplastic LEMS associated with CA who showed high levels of anti-P/Q-type voltage-gated calcium channels antibodies in the serum and cerebrospinal fluid, and reduced CMAP with increment after brief maximum voluntary contraction in electrophysiological studies. We suggest that LEMS should be considered in the differential diagnosis of patients with CA.

title: Favorable response to rituximab in a patient with anti‐VGCC‐positive Lambert‐Eaton myasthenic syndrome and cerebellar dysfunction
abstract: Lambert‐Eaton myasthenic syndrome (LEMS) is an autoimmune disease that is characterized by impaired transmission across the neuromuscular junction due to autoantibodies directed against the presynaptic voltage‐gated calcium channels (VGCC‐ab). Clinical symptoms are usually characterized by proximal muscle weakness and mild dysautonomia. In some patients there are signs of cerebellar dysfunction as well, usually associated with cancer. Here we report the long‐term follow‐up of a patient with VGCC‐ab‐positive LEMS and a severe cerebellar syndrome but without evidence of cancer over 5 years. While conventional immunosuppressive therapy (steroids, azathioprine) failed, he improved with plasma exchange and consecutive treatment with rituximab. Muscle Nerve 40: 305–308, 2009