Near-sudden unexpected death in a patient with epilepsy undergoing hemodialysis: a case report.

Sudden unexpected death in epilepsy (SUDEP) has been defined as a sudden/unexpected, witnessed/unwitnessed, nontraumatic, and nondrowning death in epileptic patients with/without seizure evidence and documented status epilepticus. Identified as the leading cause of epilepsy-related deaths, SUDEP cases are highly unrecognized and underreported due to diagnostic difficulty. We report a case of a successfully revived hemodialysis patient who developed cardiopulmonary arrest after a witnessed convulsive seizure. Electroencephalogram revealed epileptic abnormalities. Therefore, this case could be seizure-induced cardiopulmonary arrest and near-SUDEP. Hence, the possibility of SUDEP should be considered even in hemodialysis patients having conventional coronary risk factors for sudden cardiac death.

The identified clinical features of Parkinson's disease in homo-, heterozygous and digenic variants of PINK1.

To investigate the prevalence and genotype-phenotype correlations of phosphatase and tensin homolog induced putative kinase 1 (PINK1) variants in Parkinson's disease (PD) patients, we analyzed 1700 patients (842 familial PD and 858 sporadic PD patients from Japanese origin). We screened the entire exon and exon-intron boundaries of PINK1 using Sanger sequencing and target sequencing by Ion torrent system. We identified 30 patients with heterozygous variants, 3 with homozygous variants, and 3 with digenic variants of PINK1-PRKN. Patients with homozygous variants presented a significantly younger age at onset than those with heterozygous variants. The allele frequency of heterozygous variants in patients with age at onset at 50 years and younger with familial PD and sporadic PD showed no differences. [123I]meta-iodobenzylguanidine (MIBG) myocardial scintigraphy indicated that half of patients harboring PINK1 heterozygous variants showed a decreased heart to mediastinum ratio (12/23). Our findings emphasize the importance of PINK1 variants for the onset of PD in patients with age at onset at 50 years and younger and the broad spectrum of clinical symptoms in patients with PINK1 variants.

Mutations in CHCHD2 cause α-synuclein aggregation.

Mutations in CHCHD2 are linked to a familial, autosomal dominant form of Parkinson's disease (PD). The gene product may regulate mitochondrial respiratory function. However, whether mitochondrial dysfunction induced by CHCHD2 mutations further yields α-synuclein pathology is unclear. Here, we provide compelling genetic evidence that mitochondrial dysfunction induced by PD-linked CHCHD2 T61I mutation promotes α-synuclein aggregation using brain autopsy, induced pluripotent stem cells (iPSCs) and Drosophila genetics. An autopsy of an individual with CHCHD2 T61I revealed widespread Lewy pathology with both amyloid plaques and neurofibrillary tangles that appeared in the brain stem, limbic regions and neocortex. A prominent accumulation of sarkosyl-insoluble α-synuclein aggregates, the extent of which was comparable to that of a case with α-synuclein (SNCA) duplication, was observed in CHCHD2 T61I brain tissue. The prion-like activity and morphology of α-synuclein fibrils from the CHCHD2 T61I brain tissue were similar to those of fibrils from SNCA duplication and sporadic PD brain tissues. α-Synuclein insolubilization was reproduced in dopaminergic neuron cultures from CHCHD2 T61I iPSCs and Drosophila lacking the CHCHD2 ortholog or expressing the human CHCHD2 T61I. Moreover, the combination of ectopic α-synuclein expression and CHCHD2 null or T61I enhanced the toxicity in Drosophila dopaminergic neurons, altering the proteolysis pathways. Furthermore, CHCHD2 T61I lost its mitochondrial localization by α-synuclein in Drosophila. The mislocalization of CHCHD2 T61I was also observed in the patient brain. Our study suggests that CHCHD2 is a significant mitochondrial factor that determines α-synuclein stability in the etiology of PD.

[A case of isolated mycobacterial focal meningitis diagnosed on brain and meningeal biopsy].

A 76-year-old woman was admitted to our hospital because of convulsions that developed after a 1-month history of progressive right-leg palsy. MRI showed thickening of the meninges with gadolinium enhancement in the left parietal lobe and it revealed pia-subarachnoid space pattern. A lumbar puncture was performed, and cerebrospinal fluid analysis revealed no abnormality. Her serum adenosine deaminase level was elevated (28.7 IU/l). The results of serum cultures were normal. To differentially diagnose collagen disease, infection, malignancy, and inflammation of uncommon causes, we conducted brain and meningeal biopsies on the 15th hospital day. Histopathological examination of the brain tissue showed mainly necrosis and inflammation. There was severe pachymeningeal thickening without necrosis. Although it was difficult to reach a definitive diagnosis, a tissue sample taken from under the leptomeninges tested positive for mycobacterium on Ziehl-Neelsen staining. The results of polymerase chain reaction for mycobacterium were negative in the meningeal tissue. The patient received anti-tuberculous drugs, anti-nontuberculous mycobacteriosis drugs, and corticosteroids to treat Mycobacterium tuberculosis and nontuberculous mycobacterium. After starting treatment, the findings on magnetic resonance imaging improved dramatically, and no convulsions occurred during hospitalization. She was discharged on the 153rd hospital day without any neurological deficit. Because previous studies have reported that isolated mycobacterium meningitis is a diagnostically challenging condition, brain and meningeal biopsies should be considered in patients with gadolinium enhancement in the meninges.

[A case of neuro-Behçet disease presenting with a longitudinal spinal cord lesion without pain].

A 64-year-old man had transverse myelopathy that rapidly progressed without pain over the course of 1 day. The cerebrospinal fluid interleukin-6 (CSF IL-6) level was extremely high (1,120 pg/dl). Spinal cord magnetic resonance imaging (MRI) showed a longitudinal extensive lesion extending from Th8 to the conus medullaris. Despite treatment with steroids and cyclophosphamide, the symptoms worsened, and the range of sensory disturbance spread. MRI showed that the lesion expanded to Th3 over the course of 2 months. Neuro-Behçet disease (NBD) was diagnosed on basis of the high CSF IL-6 level and HLA-B51 positivity, and treatment with infliximab was begun. The sensory disturbance improved slightly, and the CSF IL-6 level fell to the normal range (7.0 pg/ml). It is important to include NBD, which rarely presents with extensive spinal cord lesion, in the differential diagnosis when patients present with acute transverse myelopathy without pain.

Stroke patients with cerebral microbleeds on MRI scans have arteriolosclerosis as well as systemic atherosclerosis.

Cerebral microbleeds (CMBs) are recognized as a manifestation of arteriolosclerosis in cerebral small vessels. However, little is known regarding whether stroke patients with CMBs often have systemic atherosclerosis. The aim of the present study was to elucidate this issue using the cardio-ankle vascular index (CAVI), a new index of systemic atherosclerosis, in acute ischemic stroke patients. We prospectively studied 105 patients (71 males, median age=70.0 years) with acute ischemic stroke. All of the patients were examined using T2*-weighted gradient echo magnetic resonance imaging (MRI) to look for and assess the CMBs and using fluid-attenuated inversion recovery to evaluate white matter hyperintensity (WMH). We assigned the patients into CMB and non-CMB groups and compared the clinical characteristics of these groups. The factors associated with CMBs were investigated using multivariate logistic regression analysis. T2*-weighted gradient echo MRI revealed CMBs in 47 patients (44.8%) and no CMBs in 58 patients (55.2%). The CAVI was significantly higher in the CMBs group (10.5 vs. 8.6, P<0.001). In the multivariate logistic regression analysis, CAVI per one point increase (odds ratio (OR), 1.50; 95% confidence interval (CI), 1.12-2.00; P=0.006), advanced WMH (OR, 4.78; 95% CI, 1.55-14.74; P=0.006) and impaired kidney function (OR, 3.31; 95% CI, 1.16-9.81; P=0.031) were independent factors associated with the presence of CMBs. A high CAVI was independently associated with CMBs in patients with acute ischemic stroke. Our results indicated that ischemic stroke patients with CMBs may have cerebral arteriolosclerosis as well as systemic atherosclerosis.

[Case of cerebral venous thrombosis causing refractory intracerebral hemorrhage].

Cerebral venous thrombosis is an uncommon disease characterized by expansive cerebral edema, venous infarction and massive intracerebral hemorrhage. Magnetic resonance imaging and angiography are useful for diagnosis of cerebral venous thrombosis. A 54-year-old man was admitted with headache, vomiting and right hemiparesis. Computed tomography (CT) revealed subcortical hematoma in the left parietal lobe. Digital subtraction angiography (DSA) demonstrated occlusion of the left Labbé vein with dilation of cortical veins and deep cerebral veins. He also suffered from pulmonary embolization and deep vein thrombosis in the lower extremities. Anticoagulant and thrombolytic agents were administered, then respiratory condition and hemiparesis were improved. However, his condition deteriolated 7 months after the initial attack. CT revealed huge subcortical hematoma in the same site. He underwent craniotomy and intracerebral hematoma was evacuated during treatment with vitamin K. His symptom gradually improved and he was discharged with moderate disability 2 months after operation. Dicision of surgical treatment is difficult because there is a risk of rebleeding due to thrombolytic therapy and progressive venous congestion. Since anticoagulant and thrombolytic therapy are inevitable, surgical indication for refractory intracerebral hemorrhage associated with cerebral venous thrombosis should be considered carefully.

Characteristics of orthostatic hypotension in Parkinson's disease.

Clinical symptoms of Parkinson's disease (PD) include not only motor distress but also autonomic dysfunction. Orthostatic hypotension (OH) occurs in one-fifth to one-half of all patients with PD. We examined the relation of this type of hypotension to clinical features and cardiovascular parameters such as cardiac 123I-meta-iodobenzylguanidine (MIBG) uptake, changes on the Valsalva maneuver, and plasma norepinephrine concentrations on head-up tilt-table testing (HUT). We performed HUT in 55 patients with PD and divided them into two groups according to the presence or absence of OH, defined as a drop in systolic blood pressure (SBP mmHg) by 20 mmHg or more on standing. We evaluated cardiac sympathetic function by 123I-MIBG scintigraphy and assessed cardiovascular autonomic function by using the Valsalva maneuver in all subjects. We also performed HUT, 123I-MIBG scintigraphy and assessed cardiovascular autonomic function by using the Valsalva maneuver in 20 controls. The results of HUT showed that 20 patients had OH and 35 did not. The hypotension was associated with gender, older age, longer disease duration, posture and gait instability phenotype, low mini-mental state examination scores and visual hallucinations. Cardiac 123I-MIBG uptakes were lower in patients with OH. SBP fell further during early second phase in patients with OH than in patients without the condition and their increase in SBP during the late second phase and the overshoot of SBP during the fourth phase were lower. The blood pressure recovery time during the fourth phase on the Valsalva maneuver was longer in patients with OH than in those without OH. There was, however, no association between the fall in SBP on HUT and baroreflex sensitivity or the plasma norepinephrine concentrations, adjusted by age, disease duration, disease severity and dopaminergic medication using multiple regression analyses. Patients without OH already had impaired cardiac sympathetic and baroreceptor reflex functions as early abnormalities of cardiovascular autonomic control. Our results suggest that pronounced vasomotor and cardiac sympathetic dysfunction is the primary cause of OH in PD, although baroreceptor reflex failure may also make a minor contribution. It was unclear whether vasomotor and cardiac sympathetic dysfunction in patients with PD was caused primarily by the impairment of preganglionic or postganglionic lesions.

Impaired cardiovascular autonomic function in Parkinson's disease with visual hallucinations.

We assessed the relations of visual hallucinations (VH) to cardiovascular autonomic dysfunction in patients with Parkinson's disease (PD). The subjects were 37 patients without VH (VH(-)) and 31 with VH (VH(+)). Autonomic function was evaluated on the basis of cardiac 123-radioiodinated metaiodobenzylguanidine (123I-MIBG) uptake and hemodynamic testing with Valsalva maneuver. Systolic blood pressure (SBP) and plasma norepinephrine concentrations (NE) were measured by tilt-table testing. 123I-MIBG uptake was lower in VH(+) than VH(-). Hemodynamic studies showed that VH(-) had only cardiac sympathetic and parasympathetic dysfunction, while VH(+) additionally had reduced vasomotor sympathetic functions. The fall in SBP during tilt-table testing was greater in VH(+) than VH(-). NE and its difference in the supine and upright positions were decreased in VH(+). We conclude that cardiac and vasomotor sympathetic dysfunction is more severe in VH(+) than in VH(-). Severe dysfunction in PD with VH is probably attributed to Lewy-body lesions or neuronal loss in sympathetic ganglia, the central autonomic system, or both.

Cardiovascular autonomic dysfunction in dementia with Lewy bodies and Parkinson's disease.

OBJECTIVE: We estimated the extent and pattern of cardiovascular autonomic dysfunction in dementia with Lewy bodies (DLB) as compared with that in Parkinson's disease (PD). METHODS: We performed meta-iodobenzylguanidine ((123)I-MIBG) scintigraphy of the heart and hemodynamic autonomic function testing using the Valsalva maneuver in 27 patients with DLB, 46 with PD, and 20 controls. RESULTS: (123)I-MIBG uptakes in DLB were reduced as compared with those in control and PD. Hemodynamic studies revealed that DLB had decreased baroreceptor reflex and reduced responses of SBP in phases II and IV as compared with PD and control. SBP responses on standing and the difference in plasma norepinephrine (NE) concentrations between supine and standing positions were reduced in PD as compared with those in control. Furthermore, SBP responses on standing, plasma NE concentrations in supine and standing positions, and the difference in plasma NE concentrations between these positions were significantly lower in DLB than in PD and control. Plasma NE concentrations in DLB with orthostatic hypotension (OH) were lower than that in DLB without OH, although some patients who had DLB with orthostatic hypotension had relatively normal plasma NE levels. CONCLUSION: Cardiovascular autonomic dysfunction is more severe in DLB than in PD and is usually caused by the loss of postganglionic sympathetic nervous function, although dysautonomia in some patients with DLB may result from preganglionic dysfunction.

Cardiovascular dysautonomia in de novo Parkinson's disease.

BACKGROUND: Clinical symptoms of Parkinson's disease (PD) include not only motor distress, but also autonomic dysfunction. OBJECTIVE: To clarify the progression of autonomic nervous dysfunction in PD. METHODS: The subjects were 44 patients with de novo PD. Autonomic nervous function, including cardiac sympathetic gain, was evaluated on the basis of cardiac radioiodinated metaiodobenzylguanidine (MIBG) uptake, the response to the Valsalva maneuver, and spectral analyses of the RR interval and blood pressure. RESULTS: Decreased cardiac MIBG uptake was found even in patients with early stage PD. MIBG uptake gradually decreased with increased disease severity. Hemodynamic studies using the Valsalva maneuver revealed that patients with early stage PD had reduced baroreceptor reflex sensitivity (BRS) in phase II, but not phase IV. Blood pressures normally rose in phases II and IV, but the increments decreased with disease progression. In early stage PD, the low frequency power of the RR interval (RR-LF) and the ratio (LF/HF) of RR-LF to the high frequency component of the RR interval (RR-HF) were significantly lower than the respective control values, despite no significant difference in RR-HF; these variables decreased with disease progression. CONCLUSION: Our results show that latent sympathetic nervous dysfunction without parasympathetic dysfunction, especially that involving the sinus node, is already present in early stage de novo PD. It is unclear whether the responsible lesion is central or peripheral.

[Cardiac sympathetic dysfunction in Parkinson's disease--relationship between results of 123I-MIBG scintigraphy and autonomic nervous function evaluated by the Valsalva maneuver].

We examined whether the results of 123I-MIBG scintigraphy reflect cardiac sympathetic nerve function in patients with Parkinson's disease (PD). The subjects were 62 patients with Parkinson's disease (age, 65.4 +/- 6.3 years) and 53 controls (65.2 +/- 7.1 years). All subjects underwent 123I-MIBG scintigraphy and QTc interval measurement on ECG. Hemodynamic autonomic function was estimated by the Valsalva maneuver in 37 subjects (63.9 +/- 5.2 years) randomly selected from the patients with PD. As control, the Valsalva maneuver was also done in 20 randomly selected controls (64.1 +/- 5.0 years), and 123I-MIBG scintigraphy was performed in 21 controls (67.7 +/- 5.3 years old). The subjects rested in a supine position for 20 min and were given an intravenous injection of 111 MBq 123I-MIBG. Relative organ uptake was determined by the region of interest (ROI) in the anterior view and the ratio of average pixel count in the heart (H) to that in the mediastinum (M) was calculated (H/M ratio) for early (after 15 min) and delayed (after 3 hrs) periods. The Valsalva maneuver was done by having the subjects exhale into a mouthpiece at an expiratory pressure of 40 mmHg for 15 seconds. Blood pressure and RR intervals were measured during the Valsalva maneuver by tonometry, using a noninvasive blood pressure monitoring system (ANS 508, Nihon Colin Co., Ltd.). Baroreceptor reflex sensitivities (BRS) of the second phase (BRS II) and fourth phase (BRS IV) of the Valsalva maneuver were calculated, and blood pressure elevations during the late second phase (IIp) and fourth phase (IVp) were measured. QTc was greater in the patients with PD (417 ms) than in the control subjects (409 ms). The H/M ratios of the early and delayed images in the patients with PD (1.76, 1.61) were significantly lower than those in the control subjects (2.56, 2.45). The early and delayed H/M ratios significantly correlated with the severity of disease according to Hoehn-Yahr stage. QTc interval and IVp significantly correlated with early and delayed H/M ratios. No other significant correlations were detected. The early H/M ratio in the patients with PD who had IVp within the normal range was lower than the early H/M ratio in control subjects. Our results show that early and delayed H/M ratio correlates with cardiac autonomic function, evaluated on the basis of QTc interval and the Valsalva maneuver, but not with baroreceptor reflex sensitivity or vasomotor autonomic function. Our findings suggest that silent cardiac autonomic dysfunction may be evaluated by 123I-MIBG scintigraphy, because early and delayed H/M ratios were lower in the patients with PD who had normal IVp than in the control subjects.

Evaluation of baroreflex sensitivity by the sequence method using blood pressure oscillations and R-R interval changes during deep respiration.

BACKGROUND: Baroreflex sensitivity assessments have been considered to be important to evaluate cardiac autonomic neuropathy. The phenylephrine method, Valsalva maneuver or sequence method at rest caused several problems. We evaluated the usefulness of the sequence method during deep respiration. METHOD: Baroreflex sensitivity was evaluated in 20 normal volunteers and 50 patients with Parkinson's disease. R-R intervals and systolic blood pressures were obtained by electrocardiogram and tonometry using a continuous blood pressure monitoring system. The sequence method is an evaluation of baroreflex sensitivity using sequences of 3 or more consecutive beats for 4 min. Baroreflex sensitivity was also assessed by the Valsalva maneuver at 5 beats before the peak systolic blood pressure of phase IV. The slope of the linear interrelationship between systolic blood pressure and the following R-R interval, i.e. baroreflex sensitivity (ms/mm Hg), was calculated with a correlation coefficient greater than 0.8. RESULT: The mean value of baroreflex sensitivity obtained by the Valsalva maneuver was 7.91 in normal volunteers and 5.35 in patients with Parkinson's disease; the one obtained by the sequence method at rest was 9.10 in normal volunteers and 8.42 in patients with Parkinson's disease, and the one obtained by the sequence method during deep respiration was 10.23 in normal volunteers and 6.73 in patients with Parkinson's disease. In some cases with Parkinson's disease, baroreflex sensitivities could not be found, whereas in all patients with Parkinson's disease, the sequence method during deep respiration could be used for evaluations. Significant correlations were found among the baroreflex sensitivities obtained by the Valsalva maneuver, and the sequence method at rest or during deep respiration in normal volunteers and patients with Parkinson's disease. CONCLUSIONS: The baroreflex sensitivity obtained by the sequence method during deep respiration could be investigated noninvasively in all cases with PD, being thus a useful method for clinical evaluation of baroreflex sensitivity.

[Sudomotor dysfunction in Parkinson's disease].

Autonomic dysfunction is often associated with the progression of Parkinson's disease (PD). The most frequent manifestations of autonomic dysfunction are cardiovascular symptoms, bladder and bowel dysfunction, and sudomotor dysfunction. However, sudomotor dysfunction in PD remains poorly understood. To evaluate sudomotor function in PD, we quantitatively measured sweating during untreated conditions in 20 patients with PD (age, 62 +/- 5 years) and in 10 age-matched control subjects (60 +/- 6 years). An evaporimeter can measure small amounts of water (g/m2h) evaporated from the body. This device was used to quantify sweating at different sites of the skin (forehead, arm, dorsal part of hand, chest wall, femur, and dorsal part of foot). Sweating demonstrated as amount of evaporated water (mean +/- SD g/m2h) was less in the patients with PD than in the control participants on the dorsal parts of the hand (13.7 +/- 5.2 vs. 23.9 +/- 5.5, p < 0.001) and foot (16.0 +/- 6.0 vs. 22.1 +/- 8.3, p < 0.05). On the dorsal part of the hand, sweating in the patients with PD at Yahr stages I and II was less than that in the control-Participants (15.2 +/- 6.3 vs. 23.9 +/- 5.5, p < 0.05). Sweating in the patients with PD at Yahr stages III and IV was less than that in the control participants on the dorsal parts of the hand (10.8 +/- vs. 2.7 vs. 23.9 +/- 5.5, p < 0.001), and foot (10.9 +/- 2.3 vs. 22.1 +/- 8.3, p < 0.005). Sweating on the dorsal part of the foot was less in the patients with PD at Yahr stages III and IV than that in those at Yahr stages I and II (10.9 +/- 2.3 vs. 18.4 +/- 6.1, p < 0.05). Sweating on the forehead in the patients with PD at Yahr stages I and II stage was slightly but not significantly less than that in the control participants (21.8 +/- 3.8 vs. 32.7 +/- 11.9, p < 0.2). Sweating on the forehead in the patients with PD at Yahr stages III and IV was sightly but not significantly greater than that in those at Yahr stages I and II (25.4 +/- 5.6 vs. 21.8 +/- 3.8, p < 0.2). Increased sweating on the forehead skin might compensate for decreased sweating on the extremital skin. Our results suggest that sudomotor dysfunction in PD primarily affects the distal parts of the upper and lower extremities. Sudomotor dysfunction affecting distal parts of the extremities worsens with increased severity of PD.