Spontaneous regression of small cell lung cancer associated with Lambert-Eaton Myasthenic Syndrome: Case report.

Spontaneous regression (SR) of cancer is very rare, especially of small cell lung cancer (SCLC). Recently, an association of paraneoplastic neurological syndrome (PNS) has been reported as a cause of SR of cancer, and onconeural antibodies are a possible factor in the SR of cancer associated with PNS. We herein report the first case of SR of SCLC combined with anti-P/Q-type of voltage-gated calcium channel (VGCC) antibody-positive Lambert-Eaton myasthenic syndrome (LEMS), a subtype of PNS. This case report suggests that SCLC may be spontaneously reduced by an autoimmune response induced by VGCC antibodies associated with LEMS. Our finding may help elucidate the mechanisms that inhibit tumor growth and cause the regression of tumors.

[A case of non-thymomatous refractory anti-AChR, Kv1.4 and titin antibodies positive generalized myasthenia gravis successfully treated by extended thymectomy].

A 74-year-old Japanese woman, who had been previously diagnosed as ocular myasthenia gravis (MG), presented to our hospital complaining of dropped head and increased fatiguability while eating. The edrophonium test was positive and decremental response was recorded on repetitive nerve stimulation. Her clinical presentation was compatible with generalized MG, and anti-AChR, Kv1.4 and titin antibodies turned out positive. Contrast enhanced CT scan showed no tumorous lesion such as thymoma. We initiated her treatment with a minimum dose of oral prednisolone. However, her condition got worse even after intravenous immune globulin and experienced myasthenic crisis twice, the former of which led to cardiopulmonary arrest. As she did not respond to traditional treatments, we determined to perform extended thymectomy. The histopathology showed atrophic change but her condition rapidly improved in several days after the operation, and soon she was weaned off the ventilator. Shortly thereafter her symptoms disappeared, followed by the titers of the antibodies above found all markedly decreased. It remains unclear how the atrophic thymus acted on the pathogenesis of refractory generalized MG.

Identification of a pre-possible multiple system atrophy phase.

OBJECTIVES: A pre-possible multiple system atrophy (MSA) phase, that is, the period between symptom onset and satisfying the second consensus diagnostic criteria for possible or probable MSA, may exist. The aim of the study was to identify the pre-possible MSA phase and to pursue the earlier diagnosis of MSA. MATERIALS & METHODS: We reviewed 52 patients with a clinical diagnosis of MSA and 430 patients showing any signs of parkinsonism, sporadic cerebellar ataxia, or autonomic failure with other clinical diagnoses. RESULTS: The pre-possible MSA phase was noted in 35 patients with a clinical diagnosis of MSA and 13 patients with other clinical diagnoses. During this phase, 16 patients presented with autonomic features first, while they presented later in 32 patients. Between these patients, there was no significant difference regarding parkinsonian, cerebellar features, levodopa response, or Babinski sign with hyperreflexia. Comparisons by autonomic features or autonomic function tests could not be performed due to the small number of patients. "Atrophy on magnetic resonance imaging of the putamen, middle cerebellar peduncle, pons, or cerebellum" and "new or increased snoring" showed high positive predictive values for MSA. CONCLUSION: A pre-possible MSA phase exists. Improved earlier diagnosis of MSA depends on the sensitivity and positive predictive value of autonomic features or autonomic function tests and on the sensitivity of "atrophy on magnetic resonance imaging of the putamen, middle cerebellar peduncle, pons, or cerebellum" and "new or increased snoring" during the pre-possible MSA phase.

Novel pathogenic VPS13A gene mutations in Japanese patients with chorea-acanthocytosis.

OBJECTIVE: To identify mutations in vacuolar protein sorting 13A (VPS13A) for Japanese patients with suspected chorea-acanthocytosis (ChAc). METHODS: We performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis of the VPS13A gene, and chorein Western blotting of erythrocyte ghosts. As the results of the analysis, 17 patients were molecularly diagnosed with ChAc. In addition, we investigated the distribution of VPS13A gene mutations and clinical symptoms in a total of 39 molecularly diagnosed Japanese patients with ChAc, including 22 previously reported cases. RESULTS: We identified 11 novel pathogenic mutations, including 1 novel CNV. Excluding 5 patients with the unknown symptoms, 97.1% of patients displayed various neuropsychiatric symptoms or forms of cognitive dysfunction during the course of disease. The patients carrying the 2 major mutations representing over half of the mutations, exon 60-61 deletion and exon 37 c.4411C>T (R1471X), were localized in western Japan. CONCLUSIONS: We identified 13 different mutations in VPS13A, including 11 novel mutations, and verified the clinical manifestations in 39 Japanese patients with ChAc.

Comparison of MRI and 123I-FP-CIT SPECT for the evaluation of MSA-P clinical severity.

The aim of the present study was to compare the efficacy of magnetic resonance imaging (MRI) and 123I-labeled 2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)nortropane single photon emission computed tomography (123I-FP-CIT SPECT) for determining the clinical severity of patients with multiple system atrophy with Parkinsonism (MSA-P). MRI and 123I-FP-CIT SPECT images from 17 patients with MSA-P as diagnosed using the Unified MSA Rating Scale part IV (UMSARS IV) score were compared. Brain MRI scans were available for all 17 patients and 123I-FP-CIT SPECT images were available for 12 patients. Putaminal atrophy (PA), hyperintense putaminal rim (HPR), hyperintense pons (hot cross bun sign, HCB), atrophy of the cerebellar vermis and hemisphere (cerebellar atrophy, CA) and other abnormalities were evaluated in the MRI scans. Distribution of striatal uptake (SU) and the specific binding ratio (SBR) on each side of the bilateral striatum were evaluated using 123I-FP-CIT SPECT images. No significant associations were observed between HPR, HCB, CA and UMSARS IV score. However, the frequency of PA increased significantly with higher UMSARS IV score (P<0.05). No significant association was observed between UMSARS IV score and SBR. The results of the present study suggest that PA, which is known to be a diagnostic indicator for MSA-P, may be used to determine the clinical severity of MSA-P with greater efficacy than other MRI findings, including HPR, HCB and CA and 123I-FP-CIT SPECT results.

Freezing of gait is an early clinical feature of progressive supranuclear palsy.

BACKGROUND AND AIM: Early clinical diagnosis of progressive supranuclear palsy (PSP) remains challenging. AIM: We attempted to identify any sign or symptom to diagnose PSP earlier. METHODS: A total of 401 patients, 40 with PSP and 361 with other neurodegenerative disorders, were included. We followed these patients for at least 1 year since 2009. We reviewed the signs and symptoms of patients with PSP in a standardized manner, and observed four manifestations: "vertical supranuclear gaze abnormality," "movement disorders," "pseudobulbar palsy" and "dementia of frontal type." Features, such as symmetric parkinsonism, freezing of gait, postural instability, dysarthria and/or dysphagia, or dementia of frontal type, were considered core clinical features. RESULTS: In patients with PSP, "movement disorders" was the most common manifestation, whereas "vertical supranuclear gaze abnormality" was uncommon during the early disease course. A total of 16 patients fulfilled the National Institute for Neurological Disorders and Stroke and Society for PSP criteria for possible PSP at their first clinic visit. Of the remaining 24 patients, 15 presented with one or more core clinical features before fulfilling the criteria for possible PSP; nine patients had a clinical diagnosis of PSP but never fulfilled the criteria. A total of 49 of the 361 patients with other neurodegenerative disorders had core clinical features. A comparison showed that freezing of gait differentiated the groups the best over the disease course. CONCLUSION: Freezing of gait is an early feature that might improve the clinical diagnosis of PSP, whereas vertical supranuclear gaze abnormality is not.

Variants associated with Gaucher disease in multiple system atrophy.

OBJECTIVE: Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case-control series. METHODS: We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants. RESULTS: In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel-Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14-5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15-5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 × 10(-3)). INTERPRETATION: The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.

A validation exercise on the new consensus criteria for multiple system atrophy.

The revised (new) consensus clinical diagnostic criteria for multiple system atrophy (MSA) were published in 2008. To validate these criteria, we utilized the same cohort that we reported previously, which included 59 patients with a clinical diagnosis of MSA that was confirmed neuropathologically in 51 of them at the Queen Square Brain Bank for Neurological Disorders. At the first clinic visit, sensitivity with new consensus possible category was higher, and PPV marginally higher, than for clinical diagnosis and old consensus possible category. New consensus probable category showed marginally higher sensitivity than, and the same PPV as, old consensus probable category. At the last clinic visit, new consensus possible category had exactly the same sensitivity and only marginally higher PPV compared with old consensus possible category. New consensus probable category showed the same sensitivity and PPV as old consensus probable category. Our data indicate that in this case material the new consensus criteria for possible MSA could improve diagnostic accuracy at first neurological evaluation compared with the old consensus criteria. Prospective clinicopathological validation studies of the new consensus criteria, particularly incorporating in vivo structural and functional imaging results, are required to extend the current findings.

Cross-sectional and longitudinal studies of three-dimensional stereotactic surface projection SPECT analysis in Parkinson's disease.

Although dementia is increasingly recognized as a common feature in Parkinson's disease (PD), its pathological substrate remains unknown. We conducted cross-sectional and longitudinal brain perfusion SPECT analyses to explore changes during the course of developing dementia in PD. Fifty-five patients originally diagnosed with PD were imaged in the cross-sectional study. Twenty-one of these, nine without dementia and 12 with dementia (PDD), were included in the longitudinal study to observe perfusion changes during the course of their disease. Data were analyzed using three-dimensional stereotactic surface projection SPECT analysis. The UK Parkinson's Disease Society Brain Bank criteria were used to diagnose PD and the revised criteria for the clinical diagnosis of dementia with Lewy bodies for PDD. The cross-sectional study showed that patients with PDD had significantly reduced perfusion in the right posterior cingulate, the right precuneus and the left posterior cingulate area. In the longitudinal study, significantly reduced perfusion was observed in the left anterior frontal gyrus in PD without dementia, and in the right inferior parietal lobule in those that developed PDD. We suggest that a relationship exists between developing dementia in PDD and reduced perfusion in the posterior parietal area.

Three-dimensional stereotactic surface projection SPECT analysis in Parkinson's disease with and without dementia.

We investigated regional cerebral blood flow (rCBF) using three-dimensional stereotactic surface projection (3D-SSP) analysis in 30 patients initially diagnosed as Parkinson's disease (PD), and compared differences in rCBF between patients with and without PD-related manifestations. 3D-SSP analysis of cerebral perfusion was performed by use of a control database. Compared to age-matched controls, there were multiple hypoperfusion areas in cases where the original diagnosis was PD. Temporal bases showed the lowest perfusion; frontal bases and medial parietal lobes the second; visual cortices the third; and parietal association areas exhibited the fourth lowest. During the clinical course, 10 of the patients suffered dementia, 9 had fluctuating cognition, and 19 experienced repeated visual hallucinations. Significant negative correlations were observed between dementia and the bilateral posterior cingulate area, and among fluctuating cognition and bilateral medial parietal lobes, parietal association areas, and dorsal occipital lobes. Repeated visual hallucinations did not show any correlation with any region of interest. We concluded that multiple hypoperfusion areas were observed in the 3D-SSP SPECT analysis. Although the presence of dementia showed a significant relationship with the bilateral posterior cingulate areas, perfusion in the frontal bases, temporal bases, or parietal lobes was markedly more reduced than that seen in the bilateral posterior cingulate areas.

Accuracy of clinical diagnosis of progressive supranuclear palsy.

We assessed the accuracy of clinical diagnosis of progressive supranuclear palsy (PSP, Steele-Richardson-Olszewski disease) and the validity of existing sets of clinical diagnostic criteria for PSP (see Appendix) using neuropathologically examined cases from the Queen Square Brain Bank for Neurological Disorders. Diagnosis of PSP was made by 40 different physicians, and 60 cases clinically diagnosed as PSP when last assessed in life were studied. In 47 cases (78%), the diagnosis of PSP was confirmed pathologically. False-positive diagnoses included Parkinson's disease with significant additional cortical Lewy body (n = 3) or Alzheimer (n = 1) pathology, multiple system atrophy (n = 4), and corticobasal degeneration, Pick's disease, motor neurone disease, cerebrovascular disease, and a sporadic case of frontotemporal dementia and parkinsonism linked to chromosome 17 (1 case each). Most cases of PSP were diagnosed accurately by neurologists at the final assessment. Although application of National Institute of Neurological Disorders and the Society for PSP possible category marginally improved the accuracy of initial clinical diagnosis, none of the existing operational criteria could significantly improve accuracy of the final clinical diagnosis.

Lack of association between progressive supranuclear palsy and arterial hypertension: a clinicopathological study.

It has been reported that up to 80% of patients clinically diagnosed as having progressive supranuclear palsy (PSP) may have arterial hypertension (HT). Because previous studies were performed on patients with presumed diagnosis of PSP, we tried to replicate these studies in a series of pathologically confirmed patients. Seventy-three patients with a neuropathological diagnosis of PSP autopsied at the Queen Square Brain Bank for Neurological Disorders in London were collected between 1989 and 1999. For the purpose of this study, patients were considered hypertensive if a blood pressure above 140/90 mm Hg was found in the clinical records. The prevalence of HT in PSP patients at the first and at the last visit during their neurological disease was compared with that found in a series of 21 normal controls who donated their brain to the same institution. Overall, 29 of 73 (39.7%) of the patients were recorded as having HT at the first visit during the disease course; this ratio increased to 42 of 73 (57.5%) at the last visit before death. When these figures were compared to the 21 normal controls (11 of 21 with HT, 52.4%), we were unable to find an increased prevalence of HT in PSP (odds ratio, 0.60; 95% confidence interval, 0.20-1.76). Therefore, HT does not represent an important clinical feature of this neurodegenerative disorder, although cerebrovascular disease can masquerade clinically as PSP.