Deep Brain Stimulation Leads to Long-term Improvement of Neuropathic Tremor due to Chronic Inflammatory Demyelinating Polyneuropathy: A Case Report.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a peripheral neuropathy caused by immune-mediated demyelination, causing tremors in 3.9%-58% of affected patients. This neuropathic tremor may persist after treatment and is known to be refractory to conventional medication. We present two cases of neuropathic tremor due to CIDP in which deep brain stimulation (DBS) over a long-term period led to marked improvement. Case 1: A 66-year-old woman presented with severe 2-3-Hz resting, postural, and kinetic tremors of both hands. The tremor was refractory to medication but improved well after bilateral VIM-DBS. However, 2 months after the procedure, the tremor worsened and was accompanied by sensory disturbance in the extremities. A diagnosis of CIDP was made, and treatment with corticosteroids and intravenous immunoglobulin achieved remission 6 months later. Although there was residual tremor after CIDP remission, it has been well controlled by DBS for the last 10 years. Case 2: A 56-year-old man presented with a 6-year history of CIDP after developing sensory dullness and tremors in the extremities. The CIDP had gone into remission 1 year previously and the sensory deficits had improved, but the tremors had gradually worsened: severe 8-12-Hz postural, kinetic, and resting tremors were present in both upper extremities. Right VIM-DBS was performed and the tremors on the left side showed marked improvement. Over the next 8 years, the tremors were well controlled and there were no relapses of CIDP. DBS may achieve long-term improvement of neuropathic tremor caused by CIDP if the CIDP is in remission.

Bilateral Low-Frequency Hearing Impairment After Microvascular Decompression Surgery.

BACKGROUND: Hearing impairment is an important complication of microvascular decompression (MVD). In patients after MVD, we have occasionally noted slight to moderate hearing deterioration at low frequencies that is difficult to detect using pure tone average. OBJECTIVE: To assess the incidence and features of low-frequency hearing impairment (LF-HI) after MVD and evaluate its associated factors. METHODS: This single-center, retrospective observational study assessed the audiometric outcome of 270 patients who underwent MVD between January 2015 and December 2020. Preoperative and postoperative hearing levels were compared for each frequency. LF-HI was defined as a hearing deterioration of ≥15 dB at 125, 250, or 500 Hz. The incidence, symptoms, and associated factors of LF-HI were analyzed. RESULTS: Statistical analysis of the patients overall demonstrated slight but significant decreases in the hearing level after MVD at lower frequencies on both the operative and contralateral sides. Eighty-one patients (30.0%) had LF-HI: 49 on the operative side, 24 on the contralateral side, and 8 on both sides, while pure tone average was worsened in 5 patients (1.8%). Subjective symptoms, including hearing deterioration, ear fullness, tinnitus, and dizziness, developed in 10.4% of the patients with LF-HI but improved subsequently within several weeks. "Older age" and "operative side" were associated with LF-HI. CONCLUSION: Decreases in lower-frequency hearing levels in both the ipsilateral and contralateral (nonoperative) ears were observed after trigeminal neuralgia and hemifacial spasm surgery. LF-HI does not cause permanent symptoms but may be a noteworthy phenomenon, possibly involved in the contralateral hearing loss encountered occasionally after other types of posterior cranial fossa surgery.

Chronic Osteomyelitis of the Cranial Vault in an Adolescent Female: A Case Report.

We report an 18-year-old female patient who developed left temporal headache and fever one month after administration of isotretinoin for acne. Imaging studies demonstrated osteolytic change in the left frontal bone, and the lesion showed gadolinium contrast enhancement. Biopsy confirmed the diagnosis of osteomyelitis, and the symptoms improved after 8 months of medication with antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs). However, the pain recurred when isotretinoin was resumed. Isotretinoin sometimes causes excessive inflammation, which may have been the reason for the osteomyelitis in this case. Although osteomyelitis is usually caused by bacterial infection, a non-bacterial mechanism should also be suspected if the condition is resistant to antibiotics.

Aspiration Surgery with Appropriate Antibiotic Treatment Yields Favorable Outcomes for Bacterial Brain Abscess.

BACKGROUND: Even in the era of advanced medical treatment, brain abscess still has a high mortality rate. At our institution, brain abscess has been treated mainly using stereotactic or echo-guided aspiration followed by relatively long-term antibiotic treatment, achieving favorable outcomes. To evaluate the efficacy of our strategy involving less-invasive aspiration surgery and long-term selective antibiotic administration for brain abscess, a single-institution series of cases was investigated. METHODS: We retrospectively reviewed and analyzed the medical records of 25 cases of brain abscess treated at Saitama Medical University Hospital between 2008 and 2021. The patients comprised 16 men and 9 women aged between 39 and 85 years (median 62 years). Neurosurgical intervention was performed for 23 (92.0%) of the patients and the remaining 2 received antibiotics alone. RESULTS: Among the neurosurgery patients, 22 (95.7%) underwent echo-guided or stereotactic aspiration, and only 1 underwent craniotomy. Anaerobic bacteria were detected in 11 patients. In the surgical and conservative groups, the median duration of antibiotic treatment was 16 weeks and 23 weeks, respectively. Since 2014 when metronidazole first became available, it has replaced meropenem to cover anaerobic bacteria. The overall mortality rate was 4.0% and a favorable outcome (Glasgow Outcome Scale 4 or 5) was achieved in 76% of the patients. There was no surgical mortality or morbidity. CONCLUSIONS: Most patients underwent aspiration surgery and achieved favorable outcomes. Along with antibiotic treatment for a sufficiently long period to cover anaerobes, this approach can be expected to yield good results.

[Technique of Microvascular Decompression for Hemifacial Spasm Based on Surgical Anatomy].

This article describes the anatomical approach and operative points of microvascular decompression for hemifacial spasm based on the author's personal experience with 1,000 cases. As vascular compression of the facial nerve is often quite caudal, it is necessary to ensure that the compressing arteries in this area are moved. Neither the vessels nor the prosthesis used to move them should not touch the root exit zone of the nerve(vascular transposition nerve isolation technique). It should also be emphasized that every effort should be made to avoid complications such as hearing impairment and postoperative subcutaneous spinal fluid accumulation.

Preservation of the Lesser Occipital Nerve Prevents Occipital Sensory Disturbance After Microvascular Decompression: Long-Term Results.

BACKGROUND: In microvascular decompression (MVD) surgery for hemifacial spasm (HFS), preservation of the lesser occipital nerve (LON) will prevent occipital sensory disturbance, a frequent complication of MVD, but the long-term outcome is unknown. This study was designed to evaluate the long-term efficacy of LON preservation. METHODS: This retrospective study included 257 patients with HFS who underwent suboccipital craniotomy with MVD. Among them, 175 were followed-up for more than 2 years. Occipital sensation was examined at 1, 12, and 24 months after MVD. The patients were classified into 3 groups based on their operative findings: LON preservation (group A; n = 112), LON not identified (group B; n = 117), and LON excision (group C; n = 28). The degree of sensory disturbance was evaluated using a visual analog scale (VAS) ranging from 1 (no sensation) to 10 (intact). RESULTS: The VAS score at 1 month was significantly better in group B (7.9 ± 0.2) than in groups A and C (7.3 ± 0.2 and 6.8 ± 0.4, respectively). At 24 months, the VAS scores were significantly higher in groups A and B (9.7 ± 0.1 and 9.7 ± 0.1) than in group C (8.8 ± 0.4), and occipital scalp sensation remained intact (VAS scores 9 and 10) in 91.9%, 92.9%, and 62.5% of the patients in groups A, B and C, respectively. CONCLUSIONS: Our long follow-up study has demonstrated that preservation of the LON during MVD prevents sensory disturbance of the occipital scalp. Efforts to preserve the LON appear to be worthwhile when the suboccipital approach is chosen.

A Large Mass Mimicking Calcified Hematoma of the Skull Showing Involvement of Myeloma Cells and a Good Response to Irradiation.

Patients with multiple myeloma often show skull bone involvement, although in most cases this is manifested as skull erosion and large masses develop only rarely. Here we report a patient who presented with a large cranial mass mimicking a subdural hematoma with calcification. The tumor shrunk with 37.5 Gy of focal irradiation in 15 fractions after biopsy. After irradiation the patient was treated with Bortezomib but died because of adverse events. The differential diagnosis of lenticular lesion of the skull and treatment strategy for large skull mass with myeloma cells are discussed.

Does arteriosclerosis contribute to hemifacial spasm?

BACKGROUND: Hemifacial spasm (HFS) is caused by pulsative vascular compression of the root exit zone (REZ) of the facial nerve. However, the mechanism that causes the offending vessels to compress the REZ has not been clarified. Elongation of intracranial arteries due to arteriosclerosis is one possibility, but such arteriosclerotic changes are not observed very frequently among patients with HFS. The aim of the present study was to investigate whether arteriosclerotic changes would contribute to the pathogenesis of HFS. METHODS: This study included 111 HFS patients, all of whom were Japanese. The prevalence rates of hypertension, hyperlipidemia, and diabetes mellitus were examined as risk factors of atherosclerosis, and the cardio-ankle vascular index (CAVI) was measured as an indicator of arteriosclerotic change. The severity of white matter lesions (WMLs) in HFS patients was measured by magnetic resonance imaging. These data were compared with data from healthy Japanese controls. RESULTS: The prevalence rates of the risk factors for atherosclerosis in the HFS patients were not higher than those in the general Japanese population. The CAVI scores for the HFS patients were similar to, or lower than those in the healthy controls for all age groups except 60 to 69-year-old men. The severity of WMLs in the HFS patients was not significantly worse than that in the controls. CONCLUSIONS: It is suggested that arteriosclerotic changes are not involved in the pathogenesis of HFS, and that vascular compression syndromes are attributable to anatomical features of the intracranial arteries and facial nerves formed during the prenatal stage.

Successful treatment of hemorrhagic congenital intracranial immature teratoma with neoadjuvant chemotherapy and surgery.

Congenital intracranial immature teratomas carry a dismal prognosis, and the usefulness of chemotherapy for these tumors has not been elucidated. The authors report on the successful management of a case of congenital intracranial immature teratoma by using neoadjuvant chemotherapy and surgery after the failure of an initial attempt at resection. The patient was an infant who had begun vomiting frequently at the age of 12 days and had been admitted to a hospital at the age of 18 days with continued vomiting, increased head circumference, and disturbance of consciousness. A CT scan of the brain revealed a large mass in his posterior fossa and hydrocephalus. Surgery was performed on an emergent basis, but only minor tumor resection could be performed due to massive intraoperative hemorrhage. The histopathological diagnosis was immature teratoma. Postoperatively, the infant was in critical condition due to severe postoperative complications, and when he was transferred to the authors' institution 43 days after birth, his respiratory condition was still unstable because of lower cranial nerve palsy. Chemotherapy with carboplatin and etoposide resulted in moderate shrinkage of the tumor. Further chemotherapy led to improvement in the patient's general condition and weight gain, which allowed for a second attempt at resection. During this second surgery, which was performed when the child was 8 months of age, after 8 courses of chemotherapy, the tumor was completely resected with little bleeding. Histological findings from the second operation were consistent with mature teratoma. This case indicates that upfront chemotherapy may be effective for the initial management of such cases. Although the objective response to the treatment was modest, chemotherapy reduced the hemorrhagic nature of the tumor, facilitated improvement of the patient's general condition, and allowed for successful resection.

Preoperative assessment of hemifacial spasm by the coronal heavily T2-weighted MR cisternography.

BACKGROUND: Microvascular decompression (MVD) has become a well-established surgical procedure for hemifacial spasm (HFS). Before surgery, it is essential to evaluate any possible deformity of the brainstem and establish the precise location of the offending vessels. In the present study of HFS patients we examined coronal sections taken by heavily T2-weighted MR cisternography in addition to routine axial sections, and assessed the usefulness of these images through comparison with intraoperative findings. METHODS: Eighty patients with HFS underwent preoperative coronal heavily T2-weighted MR cisternography before microvascular decompression surgery. Three neurosurgeons examined the preoperative axial and coronal MR images and evaluated vessel invagination into the brainstem. The usefulness of coronal sections was assessed statistically by the Mann-Whitney U test. RESULTS: Invagination of the offending vessel into the brainstem was observed in 24 cases (30.0%). In 19 patients, it was predicted preoperatively that compression of the flocculus and brainstem would be required in order to approach the offending vessels. Coronal MR cisternography was significantly more useful in cases with vessel invagination into the brainstem than in cases without invagination. CONCLUSIONS: Coronal sections obtained by MR cisternography are able to demonstrate the severity of vessel invagination into the brainstem as well as revealing the presence of the offending vessel. This information is helpful for planning a suitable approach to the root exit zone.

Pineal parenchymal tumor of intermediate differentiation with marked elevation of MIB-1 labeling index.

We report a case of pineal parenchymal tumor (PPT) in an 11-year-old girl. Brain magnetic resonance imaging (MRI) revealed a large tumor (48 mm) located in the pineal region with heterogeneous enhancement after gadolinium administration. The patient underwent tumor removal with craniotomy; only partial tumor resection could be performed because of massive intratumoral bleeding. Histopathological examination of the tumor showed lobular proliferation of round cells with moderate atypia. Cellularity varied by area, and focal Homer Wright rosettes were identified. Examination of tumor cells revealed a few mitoses (two mitotic figures per 10 high-powered fields), and immunohistochemical staining revealed positivity for synaptophysin, slight positivity for neurofilament protein (NFP) with antibody clone 2F11, and strong positivity for NFP with clone NF-M+H. The pathological diagnosis was pineal parenchymal tumor of intermediate differentiation grade II according to World Health Organization criteria despite a high (22%) MIB-1 labeling index (LI). The patient had a favorable clinical course after an intensified chemotherapy regimen designed for pineoblastoma and radiotherapy administered to the entire neuraxis, followed by stereotactic radiotherapy. In conclusion, MIB-1 LI could be a useful tool for deciding therapeutic strategies for PPT treatment when there is a discrepancy between clinical findings and pathological grading.

O6-methylguanine-DNA methyltransferase promoter methylation in 45 primary central nervous system lymphomas: quantitative assessment of methylation and response to temozolomide treatment.

Favorable responses to temozolomide chemotherapy have recently been reported in primary central nervous system lymphoma (PCNSL) patients who are refractory to high-dose methotrexate therapy. The gene encoding the DNA repair enzyme O (6)-methylguanine-DNA methyltransferase (MGMT) is transcriptionally silenced by promoter methylation in several human tumors, including gliomas and systemic lymphomas. MGMT promoter methylation is also a prognostic marker in glioblastoma patients treated with temozolomide. To validate temozolomide treatment in PCNSL, we applied methylation-sensitive high resolution melting (MS-HRM) analysis to quantitate MGMT methylation in PCNSL. MGMT promoter methylation was detected in tumors from 23 (51%) of 45 PCNSL patients, 11 of which were considered to have high (more than 70.0%) methylation status. Of the five recurrent PCNSLs treated with temozolomide, four cases responded, with three achieving complete response and one, a partial response. All four responsive PCNSLs had methylated MGMT promoters, whereas the non-responsive recurrent PCNSL did not. Thus, the use of quantitative MS-HRM analysis for the detection of MGMT promoter methylation has been suggested in PCNSL for the first time. The assay allows rapid and high-throughput evaluation of the MGMT methylation status, and seems to be promising in clinical settings. MGMT promoter methylation may become a useful marker for predicting the response of PCNSLs to temozolomide.

[Aquired stuttering in addition to a recurrence of developmental stuttering caused by brain tumor in the corpus callosum].

We reported a 66-year-old right-handed man, in whom developmental stuttering had almost been cured previously, who suffered a brain tumor. He developed not only left hemiparesis but also speech dysfluency such as acquired stuttering and aphasia. MRI showed a brain tumor in the body of the corpus callosum. The main feature of his stuttering was repetition of syllables. His stuttering was associated without secondary phenomena such as tongue clicking. His stuttering demonstrated no adaptation benefit and no consistency effect. These results suggest that the stuttering in this patient might have characteristics of both developmental and acquired stuttering, which in turn may suggest that after brain tumor, acquired stuttering occurs in addition to a recurrence of developmental stuttering.

Affinity-matured anti-glycoprotein NMB recombinant immunotoxins targeting malignant gliomas and melanomas.

Glycoprotein NMB (GPNMB), a transmembrane glycoprotein highly expressed in high-grade gliomas (HGGs), is an attractive target in cancer immunotherapy. We isolated a GPNMB-specific scFv clone, G49, from a human synthetic phage-display library. To obtain mutant single-chain variable-fragment antibodies (scFvs) with improved affinity and immunotoxins with increased activity, we subjected G49 to in vitro affinity maturation by a complementarity-determining-region (CDR) random-mutagenesis technique. Using light-chain CDR3 mutagenesis, cell-based panning by phage display, subsequent heavy-chain CDR1 mutagenesis, and flow-cytometric selection by yeast-surface display, we generated the mutant scFv clone 902V, with an overall 11-fold increase in affinity for GPNMB. Clone 902V was further randomized throughout the whole scFv by error-prone PCR, and one mutant, F6V, was selected by yeast-surface display. F6V scFv, differing from 902V by one amino-acid change in the light-chain CDR2, exhibited an affinity for GPNMB of 0.30 nM. The F6V mutant scFv clone was fused with a truncated form of Pseudomonas exotoxin A to form the immunotoxin F6V-PE38. F6V-PE38 demonstrated significant protein-synthesis-inhibition activity on GPNMB-expressing glioma and malignant melanoma cells (IC(50) = 0.5 ng/ml [8 pM]), a 60-fold improvement over G49 activity, but no cytotoxicity on GPNMB-negative cells. Furthermore, F6V-PE38 exhibited significant antitumor activity against subcutaneous malignant glioma xenografts in two nude-mouse models and a melanoma neoplastic meningitis model in athymic rats. These GPNMB-specific scFv antibodies and immunotoxins hold promise as reagents in targeted therapy for HGGs and other GPNMB-expressing malignancies.

MRP3: a molecular target for human glioblastoma multiforme immunotherapy.

BACKGROUND: Glioblastoma multiforme (GBM) is refractory to conventional therapies. To overcome the problem of heterogeneity, more brain tumor markers are required for prognosis and targeted therapy. We have identified and validated a promising molecular therapeutic target that is expressed by GBM: human multidrug-resistance protein 3 (MRP3). METHODS: We investigated MRP3 by genetic and immunohistochemical (IHC) analysis of human gliomas to determine the incidence, distribution, and localization of MRP3 antigens in GBM and their potential correlation with survival. To determine MRP3 mRNA transcript and protein expression levels, we performed quantitative RT-PCR, raising MRP3-specific antibodies, and IHC analysis with biopsies of newly diagnosed GBM patients. We used univariate and multivariate analyses to assess the correlation of RNA expression and IHC of MRP3 with patient survival, with and without adjustment for age, extent of resection, and KPS. RESULTS: Real-time PCR results from 67 GBM biopsies indicated that 59/67 (88%) samples highly expressed MRP3 mRNA transcripts, in contrast with minimal expression in normal brain samples. Rabbit polyvalent and murine monoclonal antibodies generated against an extracellular span of MRP3 protein demonstrated reactivity with defined MRP3-expressing cell lines and GBM patient biopsies by Western blotting and FACS analyses, the latter establishing cell surface MRP3 protein expression. IHC evaluation of 46 GBM biopsy samples with anti-MRP3 IgG revealed MRP3 in a primarily membranous and cytoplasmic pattern in 42 (91%) of the 46 samples. Relative RNA expression was a strong predictor of survival for newly diagnosed GBM patients. Hazard of death for GBM patients with high levels of MRP3 RNA expression was 2.71 (95% CI: 1.54-4.80) times that of patients with low/moderate levels (p = 0.002). CONCLUSIONS: Human GBMs overexpress MRP3 at both mRNA and protein levels, and elevated MRP3 mRNA levels in GBM biopsy samples correlated with a higher risk of death. These data suggest that the tumor-associated antigen MRP3 has potential use for prognosis and as a target for malignant glioma immunotherapy.

Glycoprotein nonmetastatic melanoma protein B, a potential molecular therapeutic target in patients with glioblastoma multiforme.

PURPOSE: More brain tumor markers are required for prognosis and targeted therapy. We have identified and validated promising molecular therapeutic glioblastoma multiforme (GBM) targets: human transmembrane glycoprotein nonmetastatic melanoma protein B (GPNMB(wt)) and a splice variant form (GPNMB(sv), a 12-amino-acid in-frame insertion in the extracellular domain). EXPERIMENTAL DESIGN: We have done genetic and immunohistochemical evaluation of human GBM to determine incidence, distribution, and pattern of localization of GPNMB antigens in brain tumors as well as survival analyses. RESULTS: Quantitative real-time PCR on 50 newly diagnosed GBM patient tumor samples indicated that 35 of 50 GBMs (70%) were positive for GPNMB(wt+sv) transcripts and 15 of 50 GBMs (30%) were positive for GPNMB(sv) transcripts. Normal brain samples expressed little or no GPNMB mRNA. We have isolated and characterized an anti-GPNMB polyclonal rabbit antiserum (2640) and two IgG2b monoclonal antibodies (mAb; G11 and U2). The binding affinity constants of the mAbs ranged from 0.27 x 10(8) to 9.6 x 10(8) M(-1) measured by surface plasmon resonance with immobilized GPNMB, or 1.7 to 2.1 x 10(8) M(-1) by Scatchard analyses with cell-expressed GPNMB. Immunohistochemical analysis detected GPNMB in a membranous and cytoplasmic pattern in 52 of 79 GBMs (66%), with focal perivascular reactivity in approximately 27%. Quantitative flow cytometric analysis revealed GPNMB cell surface molecular density of 1.1 x 10(4) to 7.8 x 10(4) molecules per cell, levels sufficient for mAb targeting. Increased GPNMB mRNA levels correlated with elevated GPNMB protein expression in GBM biopsy samples. Univariate and multivariate analyses correlated expression of GPNMB with survival of 39 GBM patients using RNA expression and immunohistochemical data, establishing that patients with relatively high mRNA GPNMB transcript levels (wt+sv and wt), >3-fold over normal brain, as well as positive immunohistochemistry, have a significantly higher risk of death (hazard ratios, 3.0, 2.2, and 2.8, respectively). CONCLUSIONS: Increased mRNA and protein levels in GBM patient biopsy samples correlated with higher survival risk; as a detectable surface membrane protein in glioma cells, the data indicate that GPNMB is a potentially useful tumor-associated antigen and prognostic predictor for therapeutic approaches with malignant gliomas or any malignant tumor that expresses GPNMB.