Variants in saposin D domain of prosaposin gene linked to Parkinson's disease.

Recently, the genetic variability in lysosomal storage disorders has been implicated in the pathogenesis of Parkinson's disease. Here, we found that variants in prosaposin (PSAP), a rare causative gene of various types of lysosomal storage disorders, are linked to Parkinson's disease. Genetic mutation screening revealed three pathogenic mutations in the saposin D domain of PSAP from three families with autosomal dominant Parkinson's disease. Whole-exome sequencing revealed no other variants in previously identified Parkinson's disease-causing or lysosomal storage disorder-causing genes. A case-control association study found two variants in the intronic regions of the PSAP saposin D domain (rs4747203 and rs885828) in sporadic Parkinson's disease had significantly higher allele frequencies in a combined cohort of Japan and Taiwan. We found the abnormal accumulation of autophagic vacuoles, impaired autophagic flux, altered intracellular localization of prosaposin, and an aggregation of α-synuclein in patient-derived skin fibroblasts or induced pluripotent stem cell-derived dopaminergic neurons. In mice, a Psap saposin D mutation caused progressive motor decline and dopaminergic neurodegeneration. Our data provide novel genetic evidence for the involvement of the PSAP saposin D domain in Parkinson's disease.

Clinical and genetic investigation of 17 Japanese patients with hyperekplexia.

AIM: The aim of the study was to determine clinical and genetic characteristics of Japanese patients with hyperekplexia. METHOD: Clinical courses, responses to antiepileptic drugs, outcomes, and genetic testing were investigated in 17 Japanese patients (nine males, eight females, median age 1y, range birth-45y) with hyperekplexia. RESULTS: In all patients, muscle stiffness and startle responses appeared soon after birth. Only seven patients were diagnosed with hyperekplexia before 1 year of age. Seven patients had been misdiagnosed with other disorders such as epilepsy and adult-onset anxiety neurosis. Umbilical/inguinal hernias were seen in 10 patients. Life-threatening events were noted in four patients. Clonazepam was the most effective drug. Muscle stiffness completely disappeared in 12 patients before 5 years of age, whereas startle responses resolved in only three patients. Mutations in the GLRA1 and GLRB genes were identified in 16 patients and one patient respectively. In 14 patients, the mutation showed autosomal dominant inheritance; in the other three, inheritance was autosomal recessive. p.R271Q of GLRA1 was the most frequent mutation, found in 10 patients. Novel mutations, p.A272P and p.A384P of GLRA1, were detected. Clinical severity and outcome varied even in the same family. INTERPRETATION: Early correct diagnosis is essential for prevention of accidental injuries and to provide appropriate treatments for hyperekplexia. Clonazepam is effective, although the time taken for startle responses to resolve varied.

Pallidal deep brain stimulation for patients with myoclonus-dystonia without SGCE mutations.

BACKGROUND: Pallidal deep brain stimulation (GPi-DBS) is effective for treating myoclonus and dystonia caused by SGCE mutations (DYT-SGCE, DYT11). However, it is unknown whether GPi-DBS is effective for the treatment of myoclonus-dystonia which is not associated with the SGCE gene mutations. In this study, we investigated the efficacy of GPi-DBS in treating myoclonus-dystonia in SGCE mutation-negative cases. METHODS: Three patients with myoclonus-dystonia without SGCE mutations who underwent GPi-DBS were evaluated preoperatively and 6 months postoperatively using the Unified Myoclonus Rating Scale (UMRS) and Fahn-Marsden Dystonia Rating Scale (FMDRS) for myoclonus and dystonia, respectively. In two of the three patients, myoclonus was more evident during action. Myoclonus was predominant at rest in the other patient, and he was unaware of his dystonia symptoms. The results were compared with those of the four DYT-SGCE cases. RESULTS: The mean UMRS score in patients with myoclonus-dystonia without SGCE mutations improved from 61.7 to 33.7 pre- and postoperatively, respectively, and the mean FMDRS score improved from 7.2 to 4.5. However, the degree of improvement in myoclonus-dystonia in patients without SGCE mutations was inferior to that in patients with DYT-SGCE (the UMRS score improved by 45% and 69%, respectively). CONCLUSIONS: GPi-DBS is effective for treating myoclonus-dystonia in patients with and without SGCE mutations. GPi-DBS should be considered as a treatment option for myoclonus-dystonia without SGCE mutations.

Primary progressive apraxia of speech (AOS) in a patient with Pick's disease with Pick bodies: a neuropsychological and anatomical study and review of literatures.

A 56-year-old right-handed man suffered from progressive apraxia of speech (AOS), characterized by agrammatism and buccofacial apraxia. He also became mute at the later stages of the disease progression. At autopsy, the left precentral gyrus, pars opercularis, and hippocampus showed severe atrophy. Pick bodies and Pick cells were observed. In this report, we also review previous case reports of AOS. Pick's disease is among the most commonly associated of the major diseases. Brain lesions associated with AOS may be found in regions such as the precentral gyrus and the pars opercularis in the left hemisphere.

Visual fixation suppression of caloric nystagmus in progressive supranuclear palsy - A comparison with Parkinson's disease.

BACKGROUND: Impairment of visual fixation suppression (VS) in progressive supranuclear palsy (PSP) is not well documented. OBJECTIVE: To evaluate the usefulness of impaired VS of caloric nystagmus as an index for differential diagnosis between PSP and Parkinson's disease (PD), which is often difficult, especially in the early stage. METHODS: Subjects comprised 26 PSP patients and 26 PD patients clinically diagnosed at Tokyo Metropolitan Neurological Hospital. We retrospectively investigated VS of caloric nystagmus, horizontal pursuit, saccades, and horizontal optokinetic nystagmus recorded on direct-current-electronystagmography, and neuroradiological findings. RESULTS: The median of the average VS% was 0% and 50.0% in PSP and PD patients, respectively. In PSP, VS was impaired even in the early stage of disease. We found a significant correlation between VS and velocity of saccades or maximum slow phase velocity of optokinetic nystagmus only in PSP patients. PSP patients with atrophy of the subthalamic nucleus or with decreased blood flow in the frontal lobe showed significantly more severe impairment of VS. CONCLUSIONS: VS may be a useful biomarker to differentiate patients with PSP from those with PD. Cerebellar networks that connect with the cerebral cortex and basal ganglia may contribute to impaired VS of caloric nystagmus in PSP.

Novel pathogenic mutations and copy number variations in the VPS13A gene in patients with chorea-acanthocytosis.

Chorea-acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disorder caused by loss of function mutations in the vacuolar protein sorting 13 homolog A (VPS13A) gene that encodes chorein. It is characterized by adult-onset chorea, peripheral acanthocytes, and neuropsychiatric symptoms. In the present study, we performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis, of the VPS13A gene in ChAc patients. All 73 exons and flanking regions of VPS13A were sequenced in 35 patients diagnosed with ChAc. To detect CNVs, we also performed real-time quantitative PCR and long-range PCR analyses for the VPS13A gene on patients in whom only a single heterozygous mutation was detected. We identified 36 pathogenic mutations, 20 of which were previously unreported, including two novel CNVs. In addition, we investigated the expression of chorein in 16 patients by Western blotting of erythrocyte ghosts. This demonstrated the complete absence of chorein in patients with pathogenic mutations. This comprehensive screen provides an accurate and useful method for the molecular diagnosis of ChAc.

Is Generalized and Segmental Dystonia Accompanied by Impairments in the Dopaminergic System?

Background: The pathogenesis of dystonia is remarkably diverse. Some types of dystonia, such as DYT5 (DYT-GCH1) and tardive dystonia, are related to dysfunction of the dopaminergic system. Furthermore, on pathological examination, cell loss in the substantia nigra (SN) of patients with dystonia has been reported, suggesting that impaired dopamine production may be involved in DYT5 and in other types of dystonia. Objectives: To investigate functional dopaminergic impairments, we compared patients with dystonia and those with Parkinson's disease (PD) with normal controls using neuromelanin-sensitive magnetic resonance imaging (NM-MRI) and dopamine transporter single photon emission computed tomography (DAT SPECT). Methods: A total of 18, 18, and 27 patients with generalized or segmental dystonia, patients with PD, and healthy controls, respectively, were examined using NM-MRI. The mean area corresponding to NM in the SN (NM-SN) was blindly quantified. DAT SPECT was performed on 17 and eight patients with dystonia and PD, respectively. The imaging data of DAT SPECT were harmonized with the Japanese database using striatum phantom calibration. These imaging data were compared between patients with dystonia or PD and controls from the Japanese database in 256 healthy volunteers using the calibrated specific binding ratio (cSBR). The symptoms of dystonia were evaluated using the Fahn-Marsden Dystonia Rating Scale (FMDRS), and the correlation between the results of imaging data and FMDRS was examined. Results: The mean areas corresponding to NM in the SN (NM-SN) were 31 ± 4.2, 28 ± 3.8, and 43 ± 3.8 pixels in patients with dystonia, PD, and in healthy controls, respectively. The mean cSBRs were 5 ± 0.2, 2.8 ± 0.2, 9.2 (predictive) in patients with dystonia, PD, and in healthy controls, respectively. The NM-SN area (r = -0.49, p < 0.05) and the cSBR (r = -0.54, p < 0.05) were inversely correlated with the FMDRS. There was no significant difference between the dystonia and PD groups regarding NM-SN (p = 0.28). In contrast, the cSBR was lower in patients with PD than in those with dystonia (p < 0.5 × 10-6). Conclusions: Impairments of the dopaminergic system may be involved in developing generalized and segmental dystonia. SN abnormalities in patients with dystonia were supposed to be different from degeneration in PD.

PLA2G6 variants associated with the number of affected alleles in Parkinson's disease in Japan.

This study aimed to evaluate genotype-phenotype correlations of Parkinson's disease (PD) patients with phospholipase A2 group V (PLA2G6) variants. We analyzed the DNA of 798 patients with PD, including 78 PD patients reported previously, and 336 in-house controls. We screened the exons and exon-intron boundaries of PLA2G6 using the Ion Torrent system and Sanger method. We identified 21 patients with 18 rare variants, such that 1, 9, and 11 patients were homozygous, heterozygous, and compound heterozygous, respectively, with respect to PLA2G6 variants. The allele frequency was approximately equal between patients with familial PD and those with sporadic PD. The PLA2G6 variants detected frequently were identified in the early-onset sporadic PD group. Patients who were homozygous for a variant showed more severe symptoms than those who were heterozygous for the variant. The most common variant was p.R635Q in our cohort, which was considered a risk variant for PD. Thus, the variants of PLA2G6 may play a role in familial PD and early-onset sporadic PD.

[Effects of piracetam therapy in a case of Lance-Adams syndrome].

We report a 17-year-old female patient with Lance-Adams syndrome caused by anoxic encephalopathy during a severe attack of bronchial asthma. She had difficulty in writing because of action myoclonus in her arms. She also exhibited freezing gait and was unable to walk without cane. Although her gait disturbance resembled those seen in patients with parkinsonism secondary to anoxic encephalopathy, surface electromyography revealed that it was caused by action myoclonus in her legs. The presence of giant somatosensory evoked potentials and enhanced cortical reflexes in response to the electrical stimulation to her posterior tibial nerves supported our diagnosis. A combined therapy with valproate sodium, clonazepam and piracetam (15 g/day) was not effective. However, her freezing gait remarkably improved and she was able to walk without help, after the treatment with sufficient dose of piracetam (21 g/day). Cortical hyperexcitability as revealed by electrophysiological examination also improved. We concluded that the combined therapy with antiepileptic drugs and piracetam was effective in the treatment for action myoclonus. However, because the effects seemed dose-related, the dosage of piracetam needed to be increased until the optimum effects were obtained.

Mechanisms of unilateral STN-DBS in patients with Parkinson's disease : a PET study.

Bilateral symptoms and signs of Parkinson's disease (PD) are often improved by unilateral subthalamic nucleus deep brain stimulation (STN-DBS). However, the mechanism for such bilateral effects is unknown. This study was intended to examine effects of unilateral STN-DBS using positron emission computed tomography (PET) and to elucidate mechanisms for bilateral improvement achieved by unilateral stimulation.We conducted (18)F-fluorodeoxyglucose ((18)FDG) and (18)F-fluorodopa ((18)F-DOPA ) PET scans in PD patients whose bilateral limb symptoms and axial symptoms were improved by unilateral DBS. Two scans were performed in each PET study: when DBS was on and off. We compared those images using statistic parametric mapping (SPM) 99.The significant clinical improvement obtained by unilateral DBS was shown as improvements in bilateral motor limb, axial, and gait subscores of the Unified PD Rating Scale (UPDRS). Moreover, (18)FDG PET revealed significant metabolic increases in the ipsilateral ventrolateral thalamic areas and metabolic decrease at the contralateral globus pallidus interna (GPi). In contrast, (18)F-DOPA PET showed no significant differences between DBS on and off.Ipsilateral thalamic activation might induce ipsilateral motor cortical activation, which explains the improvement of contralateral limb symptoms. Furthermore, deactivation of the contralateral GPi might disinhibit the thalamus and contralateral motor cortex, which explains reduction of ipsilateral limb symptoms. These results suggest the mechanisms for bilateral improvement achieved by unilateral DBS.

Topographic anatomy of the subthalamic nucleus localized by high-resolution human brain atlas superimposing digital images of cross-sectioned surfaces and histological images of microscopic sections from frozen cadaveric brains.

Despite the recent advent of neuro-radiographic techniques, creating a 'perfect' human brain atlas providing precise and consistent images with minimal distortion is practically difficult. In this study, we created a new human brain atlas from cadaveric brains with serial sections of 50 µm thickness covering the entire basal ganglia. Human cerebral hemispheres were obtained from 10 donated cadavers and fixed in 10% formalin solution, cut in a block measuring 50 mm × 30 mm × 50 mm around the midpoint of the anterior and posterior commissures and frozen at -40 °C. Each block was cut into 50-µm-thick sections on the freezing microtome and the cross-sectioned surface was photographed. Simultaneously, every 10th slice from one sagittal hemisphere was sampled and stained using the Kluver-Barrera method. Prepared slides were photographed under light microscopy, and data from digital images of the cross-sectioned surface (DICSS) and digital images from microscopic sections (DIMS) were processed. Gray areas on DICSS largely represented areas of dense cellularity, and around subthalamic nucleus (STN), the zona incerta and field of Forel were clearly distinguishable on the anterosuperior side, as was the substantia nigra on the caudal side. DICSS successfully delineated the anatomical structure identical to the STN and surrounding contiguous nuclei. This new brain atlas will allow elucidation of anatomy that cannot be clearly disclosed from modern radiographic imaging or is very difficult to analyze with spatially inconsistent histological sections, and will contribute to further progress in anatomical studies of the human basal ganglia.

Resting-State Pallidal-Cortical Oscillatory Couplings in Patients With Predominant Phasic and Tonic Dystonia.

Pallidal deep brain stimulation (DBS) improves the symptoms of dystonia. The improvement processes of dystonic movements (phasic symptoms) and tonic symptoms differ. Phasic symptoms improve rapidly after starting DBS treatment, but tonic symptoms improve gradually. This difference implies distinct neuronal mechanisms for phasic and tonic symptoms in the underlying cortico-basal ganglia neuronal network. Phasic symptoms are related to the pallido-thalamo-cortical pathway. The pathway related to tonic symptoms has been assumed to be different from that for phasic symptoms. In the present study, local field potentials of the globus pallidus internus (GPi) and globus pallidus externus (GPe) and electroencephalograms from the motor cortex (MCx) were recorded in 19 dystonia patients to analyze the differences between the two types of symptoms. The 19 patients were divided into two groups, 10 with predominant phasic symptoms (phasic patients) and 9 with predominant tonic symptoms (tonic patients). To investigate the distinct features of oscillations and functional couplings across the GPi, GPe, and MCx by clinical phenotype, power and coherence were calculated over the delta (2-4 Hz), theta (5-7 Hz), alpha (8-13 Hz), and beta (14-35 Hz) frequencies. In phasic patients, the alpha spectral peaks emerged in the GPi oscillatory activities, and alpha GPi coherence with the GPe and MCx was higher than in tonic patients. On the other hand, delta GPi oscillatory activities were prominent, and delta GPi-GPe coherence was significantly higher in tonic than in phasic patients. However, there was no significant delta coherence between the GPi/GPe and MCx in tonic patients. These results suggest that different pathophysiological cortico-pallidal oscillations are related to tonic and phasic symptoms.

Phenotype variability and allelic heterogeneity in KMT2B-Associated disease.

BACKGROUND: Mutations in Lysine-Specific Histone Methyltransferase 2B gene (KMT2B) have been reported to be associated with complex early-onset dystonia. Almost all reported KMT2B mutations occurred de novo in the paternal germline or in the early development of the patient. We describe clinico-genetic features on four Japanese patients with novel de novo mutations and demonstrate the phenotypic spectrum of KMT2B mutations. METHODS: We performed genetic studies, including trio-based whole exome sequencing (WES), in a cohort of Japanese patients with a seemingly sporadic early-onset generalized combined dystonia. Potential effects by the identified nucleotide variations were evaluated biologically. Genotype-phenotype correlations were also investigated. RESULTS: Four patients had de novo heterozygous mutations in KMT2B, c.309delG, c.1656dupC, c.3325_3326insC, and c.5636delG. Biological analysis of KMT2B mRNA levels showed a reduced expression of mutant transcript frame. All patients presented with motor milestone delay, microcephaly, mild psychomotor impairment, childhood-onset generalized dystonia and superimposed choreoathetosis or myoclonus. One patient cannot stand due to axial hypotonia associated with cerebellar dysfunction. Three patients had bilateral globus pallidal deep brain stimulation (DBS) with excellent or partial response. CONCLUSIONS: We further demonstrate the allelic heterogeneity and phenotypic variations of KMT2B-associated disease. Haploinsufficiency is one of molecular pathomechanisms underlying the disease. Cardinal clinical features include combined dystonia accompanying mild psychomotor disability. Cerebellum would be affected in KMT2B-associated disease.

Plasma levels of DJ-1 as a possible marker for progression of sporadic Parkinson's disease.

DJ-1 is a multifunctional protein whose loss of function by gene mutations may play a causative role for familial Parkinson's disease (PD). A recent study has shown that the expression of this molecule is upregulated in both brains and cerebrospinal fluids (CSF) in various neurological disorders, including sporadic PD, Alzheimer's disease (AD) and stroke, raising a possibility that DJ-1 could be a potential biomarker for these diseases. In this context, the main objective of the present study was to determine if DJ-1 was increased in the plasma of PD patients. For this purpose, blood plasma samples collected from sporadic PD patients, dementia with Lewy bodies (DLB) and healthy age-matched controls were analyzed by immunoblotting and enzyme-linked immunosorbent assay. The results showed that the plasma DJ-1 levels in PD (n=104) were higher than those in control (n=80) (p<0.05). Moreover, the plasma DJ-1 levels in the advanced stage of PD (n=52, Yahr III-IV) were higher than those in the early stage of PD (n=52, Yahr I-II) (p<0.05), demonstrating that the plasma DJ-1 was correlated with the disease severity in PD. Plasma DJ-1 levels were also significantly higher in DLB (n=30) compared with both controls and early stage of PD (p<0.01). Taken together, these results suggest that the plasma DJ-1 could be a useful biomarker for the evaluation of the disease severity in PD and possibly in other Lewy body diseases.

Lateral flexion in Parkinson's disease and Pisa syndrome.

Various types of abnormal posture are observed in Parkinson's disease (PD). Lateral flexion is very common and frequent among them. The clinical characteristics of lateral flexion in PD vary and are classified into two types, the chronic and subchronic types. The chronic type of lateral flexion in PD appears subclinically and worsens, which is related to the laterality of parkinsonian symptoms and the progression of the disease. The subchronic type of lateral flexion in PD develops subacutely and worsens rapidly in several months. An atypical and rare type of tonic truncal dystonia, Pisa syndrome, may be induced following the intake of neuroleptics. The clinical features of the subchronic type of lateral flexion in PD are similar to those of Pisa syndrome. Differences between lateral flexion in PD and Pisa syndrome are described.

Frequency-Specific Synchronization in the Bilateral Subthalamic Nuclei Depending on Voluntary Muscle Contraction and Relaxation in Patients with Parkinson's Disease.

The volitional control of muscle contraction and relaxation is a fundamental component of human motor activity, but how the processing of the subcortical networks, including the subthalamic nucleus (STN), is involved in voluntary muscle contraction (VMC) and voluntary muscle relaxation (VMR) remains unclear. In this study, local field potentials (LFPs) of bilateral STNs were recorded in patients with Parkinson's disease (PD) while performing externally paced VMC and VMR tasks of the unilateral wrist extensor muscle. The VMC- or VMR-related oscillatory activities and their functional couplings were investigated over the theta (4-7 Hz), alpha (8-13 Hz), beta (14-35 Hz), and gamma (40-100 Hz) frequency bands. Alpha and beta desynchronizations were observed in bilateral STNs at the onset of both VMC and VMR tasks. On the other hand, theta and gamma synchronizations were prominent in bilateral STNs specifically at the onset of the VMC task. In particular, just after VMC, theta functional coupling between the bilateral STNs increased, and the theta phase became coupled to the gamma amplitude within the contralateral STN in a phase-amplitude cross-frequency coupled manner. On the other hand, the prominent beta-gamma cross-frequency couplings observed in the bilateral STNs at rest were reduced by the VMC and VMR tasks. These results suggest that STNs are bilaterally involved in the different performances of muscle contraction and relaxation through the theta-gamma and beta-gamma networks between bilateral STNs in patients with PD.

[Unilateral subthalamic stimulation for early-stage Parkinson's disease].

According to evidenced-based criteria, surgical treatment with subthalamic stimulation is indicated for advanced Parkinson's disease with severe motor complications. Currently, the treatment is indicated for patients in whom medical treatment has failed even if the patient is still in an early stage. This study investigated the efficacy and safety of unilateral subthalamic stimulation for patients with early-stage Parkinson's disease. We evaluated the Unified Parkinson's Disease Rating Scale (UPDRS) and the Schwab England ADL score before and 6 months after this treatment in 6 patients with early-stage Parkinson's disease demonstrating predominantly unilateral parkinsonian symptoms. We implanted a stimulation electrode (model 3387 or 3389) unilaterally on the side showing dominate symptoms, using both MRI and electrophysiological guidance. Six months after the beginning of stimulation, the UPDRS motor score without medication was improved by 64% and the Schwab England ADL score was improved by 23%. There were no adverse events except for asymptomatic intra-ventricular hemorrhage in one patient. Unilateral subthalamic stimulation is a useful treatment for patients with early-stage Parkinson's disease showing predominantly unilateral parkinsonian symptoms. However, long-term results of subthalamic stimulation for early-stage patients remain unclear.

Bilateral coherence between motor cortices and subthalamic nuclei in patients with Parkinson's disease.

OBJECTIVE: It has been suggested that abnormal synchronization and oscillation of neuronal activity in the subthalamic nucleus (STN) is associated with sensorimotor dysfunction in Parkinson's disease (PD). We investigated the bilateral subcortico-cortical functional coupling in PD patients. METHODS: We simultaneously recorded local field potentials from the bilateral STN using electrodes inserted for deep brain stimulation and electroencephalograms from the bilateral motor cortices (MCx) in 11 patients at rest, and analyzed their coherences and causalities. RESULTS: Significant coherence in the sub-beta and beta frequency bands was simultaneously observed between the STN and contralateral STN (STN-cSTN), the STN and ipsilateral MCx (STN-iMCx), and the STN and contralateral MCx (STN-cMCx). In each patient, the frequency of the peak STN-cSTN coherence was similar to that of the peak STN-iMCx and STN-cMCx coherence. The causality between the STN and MCx was strongest in the one-way direction from the MCx to the ipsilateral STN. CONCLUSIONS: Abnormal oscillations in the STN in the sub-beta and beta bands were functionally coupled among bilateral STN and MCx at the eigen-frequency in individual patients with PD. SIGNIFICANCE: Synchronized activity through cortico-subcortical transmission may have an important role in the pathophysiology of PD.

Hemorrhagic complication of stereotactic surgery in patients with movement disorders.

OBJECT: Small, asymptomatic hemorrhages are easier to detect during stereotactic surgery when magnetic resonance (MR) imaging is used for targeting rather than when traditional approaches, such as ventriculography, are performed with contrast material. In the present study the authors examined the actual incidence of intraoperative hemorrhages in patients with movement disorders who had undergone MR imaging-targeted surgery, microelectrode recording (MER)-guided implantation of deep brain stimulation (DBS) electrodes, or radiofrequency-induced coagulation surgery performed. METHODS: Ninety-six consecutive patients underwent a total of 116 stereotactic operations for movement disorders (57 operations for radiofrequency-induced coagulation and 59 for DBS electrode implantation) between January 1998 and November 2002. The authors investigated the correlation between hemorrhages and other factors including the location of the hemorrhage and the type of surgery performed. Postoperative computerized tomography scans demonstrated the occurrence of intraoperative hemorrhages at 12 locations during 11 procedures (9.5% of all procedures). Nine hemorrhages occurred during 57 coagulation operations (15.8%). Within this group, the frequency of hemorrhages was highest during thalamotomy (five [21.7%] of 23 procedures) and lower during pallidotomy (four [11.8%] of 34 procedures). In contrast, only two intraventricular hemorrhages developed during 59 operations in which DBS electrodes were implanted (3.4%). In no case was hemorrhage detected in the main DBS target, that is, the subthalamic nucleus. CONCLUSIONS: When small, asymptomatic hemorrhages were included in the estimation, the actual rate of hemorrhage was higher than that previously reported. Judging from the incidence of hemorrhage during coagulation and DBS surgeries, the authors suggest that the heat induced by coagulation may play a larger role than microelectrode penetration in the development of hemorrhage.