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Intermittent administration of L-dopa in Parkinson's disease is associated with L-dopa-induced dyskinesia (LID). Long-acting dopamine agonists may reduce the risk of LID by continuous dopaminergic stimulation. We examined the LID-like behavior, preprodynorphin messenger ribonucleic acid (mRNA) expression in the striatum (a neurochemical LID hallmark), and the volume of the entopeduncular nucleus (a pathological LID hallmark) in Parkinson's disease rat models that were treated with L-dopa and cabergoline. Cabergoline co-treatment with L-dopa reduced LID, striatal preprodynorphin mRNA expression, and hypertrophy of the entopeduncular nucleus, indicating that cabergoline has an anti-LID effect independent of the L-dopa-sparing effect.

Transactivation response DNA-binding protein 43 (TDP-43)-immunoreactive neuronal cytoplasmic inclusions (NCIs) are the histopathological hallmarks of amyotrophic lateral sclerosis (ALS). They are classified as skein-like inclusions, round inclusions, dot-like inclusions, linear wisps, and diffuse punctate cytoplasmic staining (DPCS). We hypothesized that TDP-43-immunoreactive DPCS may form the early-stage pathology of ALS. Hence, we investigated phosphorylated TDP-43 pathology in the upper and lower motor neurons of patients with ALS and control participants. We designated patients whose disease duration was ≤1 year as short-duration ALS (n = 7) and those whose duration equaled 3–5 years as standard-duration ALS (n = 6). DPCS and skein-like inclusions were the most common NCIs in short-duration and standard-duration ALS, respectively. The density of DPCS was significantly higher in short-duration ALS than that in standard-duration ALS and was inversely correlated with disease duration. DPCS was not ubiquitinated and disappeared after proteinase K treatment, suggesting that it was not aggregated. Immunoelectron microscopy revealed that DPCS corresponded to nonfibrillar TDP-43 localized to the ribosomes of the rough endoplasmic reticulum (ER). These findings suggest that nonfibrillar TDP-43 accumulation in the rough ER is the earliest TDP-43 pathology in ALS, which may be helpful in developing future TDP-43 breakdown strategies for ALS.

Aims: Synaptic dysfunction in Parkinson's disease is caused by propagation of pathogenic alpha-synuclein between neurons. Previously, in multiple system atrophy (MSA), pathologically characterised by ectopic deposition of abnormal alpha-synuclein predominantly in oligodendrocytes, we demonstrated that the occurrence of memory impairment was associated with the number of alpha-synuclein-positive neuronal cytoplasmic inclusions (NCIs) in the hippocampus. In the present study, we aimed to investigate how abnormal alpha-synuclein in the hippocampus can lead to memory impairment., Methods: We performed pathological and biochemical analyses using a mouse model of adult-onset MSA and human cases (MSA, N = 25; Parkinson's disease, N = 3; Alzheimer's disease, N = 2; normal controls, N = 11). In addition, the MSA model mice were examined behaviourally and physiologically., Results: In the MSA model, inducible human alpha-synuclein was first expressed in oligodendrocytes and subsequently accumulated in the cytoplasm of excitatory hippocampal neurons (NCI-like structures) and their presynaptic nerve terminals with the development of memory impairment. alpha-Synuclein oligomers increased simultaneously in the hippocampus of the MSA model. Hippocampal dendritic spines also decreased in number, followed by suppression of long-term potentiation. Consistent with these findings obtained in the MSA model, post-mortem analysis of human MSA brain tissues showed that cases of MSA with memory impairment developed more NCIs in excitatory hippocampal neurons along with alpha-synuclein oligomers than those without., Conclusions: Our results provide new insights into the role of alpha-synuclein oligomers as a possible pathological cause of memory impairment in MSA.

Non-motor symptoms (NMSs) negatively impact the health-related quality of life (HrQOL) of patients with Parkinson’s disease (PD). The Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) is a comprehensive scale for evaluating PD. It remains unclear whether the NMSs evaluated with MDS-UPDRS are predictive of HrQOL. This study aimed to investigate whether NMSs, as evaluated with the MDS-UPDRS, could predict the HrQOL of patients with PD. We conducted a 2-year retrospective observational cohort study assessing 108 patients with PD who were recruited from a single tertiary center between January 2015 and December 2017. MDS-UPDRS was used to assess NMSs and motor symptoms and Parkinson’s Disease Questionnaire-39 (PDQ-39) to measure patients’ HrQOL. The median age of patients was 69 years, and 65.7% were female. The median MDS-UPDRS part I, part II, part III, and PDQ-39-summary index scores were 8, 10, 22, and 25, respectively. The final stepwise multiple linear regression model showed that female sex (standard partial regression coefficient β = 0.131, P

BackgroundIt remains unclear why patients with young-onset Parkinson’s disease more often develop levo-dihydroxyphenylalanine (L-dopa)-induced dyskinesia (LID) and have a more severe form than patients with old-onset Parkinson’s disease. Previous studies using animal models have failed to show young-onset Parkinson’s disease enhances LID.ObjectivesTo evaluate the association of age at dopaminergic denervation (onset age) and initiation of L-dopa treatment (treatment age) with LID development in model rats.MethodsWe established rat models of young- and old-lesioned Parkinson’s disease (6-hydroxydopamine lesions at 10 and 88 weeks of age, respectively). Dopaminergic denervation was confirmed by the rotational behavior test using apomorphine. Rats in the young-lesioned group were allocated to either L-dopa treatment at a young or old age, or saline treatment. Rats in the old-lesioned group were allocated to either L-dopa treatment or saline group. We evaluated L-dopa-induced abnormal involuntary movements during the 14-day treatment period. We also examined preprodynorphin mRNA expression in the striatum (a neurochemical hallmark of LID) and the volume of the medial globus pallidus (a pathological hallmark of LID).ResultsLID-like behavior was enhanced in L-dopa-treated young-lesioned rats compared with L-dopa-treated old-lesioned rats. Preprodynorphin mRNA expression was higher in L-dopa-treated young-lesioned rats than in in L-dopa-treated old-lesioned rats. The volume of the medial globus pallidus was greater in L-dopa-treated young-lesioned rats than in L-dopa-treated old-lesioned rats. Treatment age did not affect LID-like behavior or the degree of medial globus pallidus hypertrophy in the young-lesioned model.ConclusionBoth dopaminergic denervation and L-dopa initiation at a young age contributed to the development of LID; however, the former may be a more important factor.

Tumor necrosis factor-alpha (TNF-α) inhibitors are increasingly used for various autoimmune diseases. Demyelinating events in the CNS, including myelitis, are reportedly associated with TNF-α inhibitor exposure. Behcet's disease rarely involves the spinal cord. A 51-year-old Japanese woman presented with back pain, leg weakness, and numbness during golimumab administration, a TNF-α inhibitor, for Behcet's disease. Magnetic resonance imaging revealed multifocal myelitis in the cervical and thoracic spinal cords. Discontinuation of golimumab and steroid therapy were effective and the symptoms have not relapsed. Although it is possible that the patient's myelitis was part of the symptoms of neuro-Behcet's disease, we believe that golimumab likely played a role in the myelitis development.

Background Hyperthermia in patients with acute ischemic stroke is associated with poor outcome. Although previous studies have shown a negative effect on functional outcome, even in patients treated with intravenous recombinant tissue plasminogen activator (rt-PA), the effect on survival remains unclear. Aims of the study The aim of this study was to evaluate the association between the functional and survival prognosis and hyperthermia in patients with acute ischemic stroke treated with rt-PA. Methods We studied 120 patients treated with rt-PA from 2306 consecutive Japanese patients with acute cerebral infarction at Aomori Prefectural Central Hospital between December 2009 and March 2017. We defined hyperthermia as ≥38°C within 72 hours after rt-PA administration. Propensity score matching was used to compare 34 non-hyperthermia and hyperthermia patient pairs. Results Final modified Rankin Scale scores were higher in the hyperthermia group than in the non-hyperthermia group. In addition, the Kaplan-Meier model showed that the non-hyperthermia group had significantly better survival rates than the hyperthermia group (hazard ratio, 5.3; 95% confidence intervals, 1.2-24.8). Conclusions Hyperthermia within 3 days after rt-PA is associated with poor functional prognosis and survival outcome in patients with acute cerebral infarction.

Miller Fisher syndrome (MFS) can be difficult to diagnose, particularly in mild cases where some of the standard triad of symptoms (external ophthalmoplegia, ataxia, and loss of deep tendon reflex) are absent. We herein report a case of the incomplete form of MFS diagnosed in a 54-year-old Japanese man who presented only with ataxia symptoms and was positive for the anti-GQ1b antibody. However, the patient also suffered from dysgeusia, a significant impairment of taste perception. We propose that dysgeusia in acute-onset ataxia cases may constitute an important clinical feature to aid in the diagnosis of the incomplete form of MFS.

The mechanisms of dopamine dysregulation syndrome (DDS) in Parkinson's disease (PD) remain unclear, although it is known that the nucleus accumbens (NAc) plays a role in its development. Based on the hypothesis that DDS and levodopa-induced dyskinesia (LID) share a pathophysiological basis, we investigated dendritic spine morphology of medium spiny neurons (MSNs) in the NAc of a rat model of LID, because spine enlargement in MSNs of the caudate/putamen has been proposed to be a morphological hallmark of LID. Spines of NAc MSNs also became enlarged in the LID model. This result suggests that excitatory supersensitivity of MSNs in the NAc is involved in the development of DDS, similar to what occurs in the caudate/putamen in LID.

A 60-year-old female was treated for depression with the antidepressant paroxetine for 13 years. The patient had experienced clumsiness and mild rigidity in the left hand, and had agraphia and mild subjective memory complaints for 3 years prior to admission in our hospital. She experienced exacerbated depression that included worsened depressive mood, lowered motivation, and suicidal ideation without precipitating stressful life events for 2 years prior to admission, and although she had continued taking the antidepressant, these symptoms were not ameliorated by increasing the dose of paroxetine. Following the development of myoclonus and pain in her left arm, we performed magnetic resonance imaging of her head, that revealed diffuse atrophy and right parietal lobe atrophy. The patient was ultimately diagnosed with corticobasal degeneration (CBD). Her left arm myoclonus and depression improved following levodopa administration. Therefore, we concluded that the recurrent depression may have been induced by CBD.

• Serotonin and norepinephrine transporters are capable of dopamine reuptake in the parkinsonian striatum.

Long-term administration of levodopa for Parkinson's disease is associated with various motor and non-motor complications. We examined the dendritic spine morphology of pyramidal tract-type neurons in the prefrontal cortex in a rat model of Parkinson's disease chronically treated with levodopa. Dendritic spines showed decreased density and increased average volume after dopamine denervation and levodopa treatment. These morphologic alterations suggest that the prefrontal neurons may maladaptively respond to excitatory input, which might be one of the mechanisms underlying various levodopa-induced complications in patients with Parkinson's disease.

A 72-year-old woman presented with a 6-week history of gait disturbance and mild disturbance of consciousness. For 9 months, she had been treated for advanced non-small cell lung cancer with atezolizumab. MRI revealed symmetrical high signal in the thalamus bilaterally (figure). She did not have evidence of cancer recurrence or metastases. Serum autoimmune antibodies were absent (anti-AQP4, anti-MOG, anti-amphiphysin, CV2, PNMA2 [Ma2/Ta], Ri, Yo, Hu, recoverin, SOX1, titin, zic4, GAD65, and Tr [DNER]). In the CSF, she had high immunoglobulin G index and positive oligoclonal bands but normal myelin basic protein, absent anti-NMDA receptor and anti-MOG antibodies, and no evidence of infection. Cytology was normal. She was diagnosed with autoimmune encephalitis associated with atezolizumab treatment and treated with steroids and IV immunoglobulin 9 weeks after the onset of symptoms. The size of the lesions decreased after immunotherapy started, but she remained bedridden.

Objectives: Physician-staffed helicopter transport is faster than ground transport and allows for prompt medical care of patients in rural areas. In this study, we evaluated the relationship between helicopter transport and the prognosis of patients with acute cerebral infarction in rural Japan. Methods: This retrospective, observational study included 546 patients with acute cerebral infarction attending Aomori Prefectural Central Hospital, which serves a rural region of Japan. Patients were separated into 2 transport groups: physician-staffed helicopter emergency medical services and ground emergency medical services. Patients were assessed for stroke severity, treatment, and prognosis. Results: Of the 546 patients, 11.2% were transported by physician-staffed helicopter emergency medical services and 88.8% by ground emergency medical services. Although the distance transported was significantly longer in the physician-staffed helicopter emergency medical services group, the time from onset to reaching our hospital was similar between the groups. National Institutes of Health Stroke Scale on admission and final prognosis were significantly worse with physician-staffed helicopter emergency medical services than with ground emergency medical services. Multivariate analysis showed no association between transport system and prognosis. Conclusions: In this study, patients transported by physician-staffed helicopter emergency medical services had more severe stroke symptoms and poorer functional outcomes than those transported by ground emergency medical services. However, the transport time was shorter for physician-staffed helicopter emergency medical services; thus, physician-staffed helicopter emergency medical services may be useful for reducing transport time for patients in rural Japan.

Subacute sensory ataxic neuronopathy is a well-known form of paraneoplastic syndrome. Most sensory neuronopathies are associated with small cell lung cancer and anti-Hu antibodies, and usually show only slight improvement with immunotherapy. To date, there have been few reports of neuropathy associated with thymoma and no treatment strategy has been established for thymoma-related neuropathy. Here, we provide the first report of a case of sensory ataxic neuronopathy with thymoma that showed marked improvement after steroid therapy, even though preceding intravenous immunoglobulin treatments and tumor resection were less effective. A 57-year-old Japanese man was referred to our hospital with a 6-week history of distal paresthesia in his four limbs and an unsteady gait. He presented with left-dominant ataxia in his four limbs due to reduced sensation in his extremities. He also complained of constipation, difficulty urinating, and erectile dysfunction. Upon investigation, including electrodiagnostic studies, the patient was diagnosed as having sensory ataxic neuronopathy with invasive thymoma. A first round of intravenous immunoglobulin therapy, a following thymectomy, and a second round of intravenous immunoglobulin therapy after the surgery were not effective in treating his neurological symptoms. Subsequently, oral steroid therapy was started, which brought about a remarkable improvement; 6 weeks after the beginning of the steroid therapy, his neurological symptoms were resolved, except for slight distal paresthesia in his feet. Although rarely reported, thymoma can underlie sensory neuronopathy, and the response of thymoma-associated sensory neuronopathy to immunotherapy might be better than that of anti-Hu antibody-related neuropathies. Even if the first immunotherapy is not effective in treating neuropathy with thymoma, further immunomodulatory treatment should be tried after treating the tumor.

INTRODUCTION The loss of epidermal nerve fibers is regarded as an early pathological change in human diabetes. We investigated epidermal Aδ nerve fiber function by examining pain threshold by means of intraepidermal electrical stimulation (IES) in early diabetic neuropathy. METHODS We recruited 20 asymptomatic diabetic patients. Eighteen age-matched, healthy subjects served as controls. We placed the IES electrode onto the skin of the foot dorsum and delivered weak electrical stimulation. We defined pain threshold as the minimum electrical intensity at which a subject felt a pricking sensation. RESULTS The mean pain thresholds in the patient group were significantly higher (0.053 ± 0.036 mA; P

A 51-year-old Japanese woman was admitted to our hospital because of speech difficulty following severe headache. Neurological examination showed dysarthria and tongue weakness on the right side, indicating right hypoglossal nerve palsy. Needle electromyography of the right side of the tongue showed fibrillation potentials. Magnetic resonance angiography and computed tomography angiography revealed a right, persistent, primitive hypoglossal artery (PPHA) that met Lie's diagnostic criteria. Digital subtraction angiography showed an extended PPHA with irregular caliber in the portion running through the right hypoglossal canal. We diagnosed compression neuropathy of the hypoglossal nerve due to PPHA enlargement based on the findings of ipsilateral hypoglossal nerve palsy, fibrillation that indicated peripheral nerve palsy, and the enlarged diameter of the portion of the PPHA running through the right hypoglossal canal. We prescribed antihypertensive therapy. At 1 year after onset, her tongue weakness was alleviated. Clinicians should consider compression neuropathy due to a PPHA as one of the possibilities in the differential diagnosis of hypoglossal nerve palsy.

Background. It is often difficult to differentiate Parkinson’s disease (PD) from multiple system atrophy (MSA), especially in their early stages.Objectives. To examine the clinical utility of histopathological analysis of biopsied skin from the chest wall and/or leg in differentiating between the two diseases.Methods. Skin biopsies from the lower leg and/or anterior chest wall were obtained from 38 patients with idiopathic PD (26 treated with levodopa and 12 levodopa-naïve) and 13 age-matched patients with MSA. We sought aggregates of phosphorylatedα-synuclein on cutaneous nerve fibers using double fluorescence immunohistochemistry and confocal microscopy and measured intraepidermal nerve fiber density (IENFD).Results. Phosphorylatedα-synuclein aggregates were identified on cutaneous nerves in two patients with PD (5.3%) but in none of the patients with MSA, and IENFD was significantly lower in patients with PD when compared to those with MSA. There was no difference in IENFD between levodopa-treated and levodopa-naïve patients with PD.Conclusions. Our findings suggest that an assessment of IENFD in biopsied skin could be a useful means of differentiating between PD and MSA but that detection ofα-synuclein aggregates on cutaneous nerves in the distal sites of the body is insufficiently sensitive.

Objectives Few studies have investigated the risk factors for motor vehicle accidents (MVA) in individuals with Parkinson's disease (PD) in Japan. Materials and Methods We sent an anonymous questionnaire to 1417 patients with PD who had received medical care certificates for Intractable Diseases during the 2014 fiscal year from the Aomori Prefectural Government in Japan. Data from patients with PD who previously or currently held a driving license at the time of the survey were analyzed. Results Complete datasets were obtained from 384 patients with PD who were either past or present driving license holders. Fifty-seven patients had caused at least one MVA in the last 5 years before the survey. Logistic regression analyses revealed that ergot-dopamine agonist (DA) use and excessive daytime sleepiness (Epworth Sleepiness Scale score ≥ 10) were the best predictors of MVAs. Patients having caused non-sleep-related MVAs had significantly longer disease durations, more frequent ergot-DA use, and higher cognition and communication subscores on the Parkinson's Disease Questionnaire-39 than those without non-sleep-related MVAs (P

Parkinson's disease (PD) is a neurodegenerative disorder associated with the progressive loss of nigrostriatal dopaminergic neurons. Levodopa is the most effective treatment for the motor symptoms of PD. However, chronic oral levodopa treatment can lead to various motor and nonmotor complications because of nonphysiological pulsatile dopaminergic stimulation in the brain. Examinations of autopsy cases with PD have revealed a decreased number of dendritic spines of striatal neurons. Animal models of PD have revealed altered density and morphology of dendritic spines of neurons in various brain regions after dopaminergic denervation or dopaminergic denervation plus levodopa treatment, indicating altered synaptic transmission. Recent studies using rodent models have reported dendritic spine head enlargement in the caudate‐putamen, nucleus accumbens, primary motor cortex, and prefrontal cortex in cases where chronic levodopa treatment following dopaminergic denervation induced dyskinesia‐like abnormal involuntary movement. Hypertrophy of spines results from insertion of alpha‐amino‐2,3‐dihydro‐5‐methyl‐3‐oxo‐4‐isoxazolepropanoic acid receptors into the postsynaptic membrane. Such spine enlargement indicates hypersensitivity of the synapse to excitatory inputs and is compatible with a lack of depotentiation, which is an electrophysiological hallmark of levodopa‐induced dyskinesia found in the corticostriatal synapses of dyskinetic animals and the motor cortex of dyskinetic PD patients. This synaptic plasticity may be one of the mechanisms underlying the priming of levodopa‐induced complications such as levodopa‐induced dyskinesia and dopamine dysregulation syndrome. Drugs that could potentially prevent spine enlargement, such as calcium channel blockers, N‐methyl‐D‐aspartate receptor antagonists, alpha‐amino‐2,3‐dihydro‐5‐methyl‐3‐oxo‐4‐isoxazolepropanoic acid receptor antagonists, and metabotropic glutamate receptor antagonists, are candidates for treatment of levodopa‐induced complications in PD. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Growing evidence suggests that abnormal synaptic plasticity of cortical neurons underlies levodopa-induced dyskinesia (LID) in Parkinson's disease (PD). Spine morphology reflects synaptic plasticity resulting from glutamatergic transmission. We previously reported that enlargement of the dendritic spines of intratelencephalic-type (IT) neurons in the primary motor cortex (M1) is linked to the development of LID. However, the relevance of another M1 neuron type, pyramidal-tract (PT) neurons, to LID remains unknown. We examined the morphological changes of the dendritic spines of M1 PT neurons in a rat model of LID. We quantified the density and size of these spines in 6-hydroxydopamine-lesioned rats (a model of PD), 6-hydroxydopamine-lesioned rats chronically treated with levodopa (a model of LID), and control rats chronically treated with levodopa. Dopaminergic denervation alone had no effect on spine density and head area. However, the LID model showed significant increases in the density and spine head area and the development of dyskinetic movements. In contrast, levodopa treatment of normal rats increased spine density alone. Although, chronic levodopa treatment increases PT neuron spine density, with or without dopaminergic denervation, enlargement of PT neuron spines appears to be a specific feature of LID. This finding suggests that PT neurons become hyperexcited in the LID model, in parallel with the enlargement of spines. Thus, spine enlargement, and the resultant hyperexcitability of PT pyramidal neurons, in the M1 cortex might contribute to abnormal cortical neuronal plasticity in LID.

The efficacy of LSVT-BIG for advanced Parkinson’s disease (PD) patients with wearing off remains to be determined. Therefore, we evaluated whether LSVT-BIG improves motor disability in eight PD patients with wearing off. Unified Parkinson’s Disease Rating Scale (UPDRS) scores, daily off time, and mobility assessments were evaluated during the “on” time before and after the LSVT-BIG course. LSVT-BIG significantly improved UPDRS III scores at 4 weeks and UPDRS II scores in the “off” state at 12 weeks, with no changes in the other measures. The findings suggest that LSVT-BIG may be an effective therapy for advanced PD patients with wearing off.

Maladaptive plasticity at corticostriatal synapses plays an important role in the development of levodopa-induced dyskinesia. Recently, it has been shown that synaptic plasticity is closely linked to morphologic changes of dendritic spines. To evaluate morphologic changes of dendritic spines of two types of striatal medium spiny neurons, which project to the internal segment of globus pallidus or the external segment of globus pallidus, in the levodopa-induced dyskinesia model, we used 6-hydroxydopamine-lesioned rats chronically treated with levodopa. Dendritic spines were decreased and became enlarged in the direct pathway neurons of the model of levodopa-induced dyskinesia. The same levodopa treatment to normal rats, in which no dyskinesia was observed, also induced enlargement of dendritic spines, but not a decrease in density of spines in the direct pathway neurons. These results suggest that a loss and enlargement of dendritic spines in the direct pathway neurons plays important roles in the development of levodopa-induced dyskinesia.

Levodopa-induced dyskinesia has been suggested to result from maladaptive plasticity at corticostriatal synapses. Synaptic plasticity is based upon morphologic changes of dendritic spines. To elucidate whether the morphologic changes of spines occur in the striatum of rat models of levodopa-induced dyskinesia, we examined immunoreactivity of drebrin, an actin-binding protein localized in dendritic spines of excitatory synapses, using 6-hydroxydopamine-lesioned rats repeatedly treated with levodopa. The cross-sectional area of drebrin-immunoreactive organelles, putative spines, in the dopamine-denervated striatum of the levodopa-induced dyskinesia model was greater than that of the Parkinson's disease model. Immunoelectron microscopic examinations confirmed that drebrin-immunoreactive spines became enlarged in the dopamine-denervated striatum of the levodopa-induced dyskinesia model, but not in the Parkinson's disease model. These results suggest that the development of levodopa-induced dyskinesia is associated with enlargement of dendritic spines at corticostriatal excitatory synapses.

We report a family of intravenous immunoglobulin (IVIg)-responsive X-linked Charcot-Marie-Tooth disease Type 1 (CMT1X) with a novel gap junction protein 1 mutation. Two of three siblings in the family complained of subacute motor and sensory impairment, and their symptoms improved after the administration of IVIg. Additional IVIg treatment also resulted in similar improvement. The other also showed a mild improvement on IVIg. It has been suggested that an immune-mediated process is involved in the progression of neuropathy in CMT1X. The finding in our report provides evidence of susceptibility to immune-mediated demyelinating neuropathy in some form of CMT1X. Superimposed demyelinating neuropathy as well as a gradual deterioration of neuropathy over decades can be a clinical manifestation of CMT1X.

No source of bleeding is detected by angiogram in 15-20% of patients with nonaneurysmal subarachnoid hemorrhage (SAH). This negative angiographic finding might suggest a benign prognosis. We describe a case of fatal SAH caused by Aspergillus arteritis without formation of fusiform dilatation or aneurysms. A 76-year-old man with a 2-month history of progressive visual loss due to pachymeningitis around the optic nerves suffered from SAH in the bilateral sylvian fissures. Repetitive serum galactomannan assay and angiography showed no abnormality. Post mortem examination revealed marked proliferation of Aspergillus in the granulomas of the frontal base dura mater. In addition, major trunks and several branches of the bilateral middle cerebral arteries were invaded by Aspergillus hyphae, which destroyed the walls in the absence of dilatation and aneurysms. Invasive aspergillosis of the CNS often forms a mycotic aneurysm. However, four autopsy cases of nonaneurysmal SAH due to invasive aspergillosis have been reported. The present case is the second autopsy case of Aspergillus arteritis without angiographic abnormality, resulting in fatal SAH. Aggressive and continuous antifungal therapy is absolutely necessary in suspected cases of invasive aspergillosis of the CNS, even if angiography is negative and therapeutic markers of aspergillosis are normal.