Efficacy and tolerability of 100†mg of lasmiditan for migraine: A multi-center, prospective observational real-world study in Japan.

BACKGROUND: Real-world data on the effectiveness and safety of lasmiditan, a new medication for acute migraine attacks, is necessary. METHODS: We performed a prospective, observational, multi-center, real-world study. A total of 48 patients with migraine (44 females, 44.6 ± 12.9 years old) were included in this study. RESULTS: Twenty-three patients (47.9%) reported they were headache-free two hours after taking lasmiditan and were categorized into the responder group. In total, 44 patients (91.7%) experienced at least one side effect within two hours of taking the medication. Dizziness, somnolence, malaise, nausea, and palpitations were reported by 56.3% (n = 27), 45.8% (n = 22), 37.5% (n = 18), 20.8% (n = 10), and 14.6% (n = 7) of patients respectively. Of 48 patients, 20 (41.7%) indicated that they preferred lasmiditan to their previous acute treatment. There were no predictive factors for efficacy. CONCLUSION: This real-world study demonstrated the efficacy and safety of lasmiditan. More than 90% of patients experienced side effects from lasmiditan. Approximately 40% of patients preferred lasmiditan despite the occurrence of side effects.

Flexible modeling of headache frequency fluctuations in migraine with hidden Markov models.

OBJECTIVE: To explore hidden Markov models (HMMs) as an approach for defining clinically meaningful headache-frequency-based groups in migraine. BACKGROUND: Monthly headache frequency in patients with migraine is known to vary over time. This variation has not been completely characterized and is not well accounted for in the classification of individuals as having chronic or episodic migraine, a diagnosis with potentially significant impacts on the individual. This study investigated variation in reported headache frequency in a migraine population and proposed a model for classifying individuals by frequency while accounting for natural variation. METHODS: The American Registry for Migraine Research (ARMR) was a longitudinal multisite study of United States adults with migraine. Study participants completed quarterly questionnaires and daily headache diaries. A series of HMMs were fit to monthly headache frequency data calculated from the diary data of ARMR. RESULTS: Changes in monthly headache frequency tended to be small, with 47% of transitions resulting in a change of 0 or 1 day. A substantial portion (24%) of months reflected daily headache with individuals ever reporting daily headache likely to consistently report daily headache. An HMM with four states with mean monthly headache frequency emissions of 3.52 (95% Prediction Interval [PI] 0-8), 10.10 (95% PI 4-17), 20.29 (95% PI 12-28), and constant 28 days/month had the best fit of the models tested. Of sequential month-to-month headache frequency transitions, 12% were across the 15-headache days chronic migraine cutoff. Under the HMM, 38.7% of those transitions involved a change in the HMM state, and the remaining 61.3% of the time, a change in chronic migraine classification was not accompanied by a change in the HMM state. CONCLUSION: A divide between the second and third states of this model aligns most strongly with the current episodic/chronic distinction, although there is a meaningful overlap between the states that supports the need for flexibility. An HMM has appealing properties for classifying individuals according to their headache frequency while accounting for natural variation in frequency. This empirically derived model may provide an informative classification approach that is more stable than the use of a single cutoff value.

The impact of pre-morbid headaches on headache features and long-term health outcomes following traumatic brain injury: Insights from the American Registry for Migraine Research.

OBJECTIVE: To investigate the impact of having headaches prior to traumatic brain injury (TBI) on headache features and long-term patient health outcomes. BACKGROUND AND METHODS: This was an exploratory analysis of patients with TBI who were enrolled in the American Registry for Migraine Research (ARMR), a multicenter, prospective, longitudinal patient registry composed of patients with International Classification of Headache Disorders, 3rd edition (ICHD-3)-defined headache diagnoses. The ARMR study enrolled 2,707 patients between February 1, 2016 and May 6, 2020, 565 of whom qualified for this analysis. Those with headaches prior to their TBI were compared to those without headaches prior to their TBI for ICHD-3 diagnoses, headache frequency and intensity, headache-related disability (Migraine Disability Assessment score), symptoms of anxiety (General Anxiety Disorder [GAD-7]), depression (two items from Patient Health Questionnaire-9), post-traumatic stress disorder (PTSD), cutaneous allodynia (12-item Allodynia Symptom Checklist [ASC-12]), cognitive dysfunction (Migraine Attacks Subjective Cognitive Impairments Scale [Mig-SCog]), pain interference (Patient-Reported Outcomes Measurement Information System-Pain Interference), and work productivity (Work Productivity and Activity Impairment). RESULTS: Among 565 participants with TBI, 350 had headaches prior to their TBI. Those with pre-TBI headaches were less likely to receive a diagnosis of post-traumatic headache (PTH; 14/350 [4.0%] vs. 21/215 [9.8%], p = 0.006), even though 25.7% reported new or worsening headaches within 7 days of their TBI. Those with pre-TBI headaches had higher ASC-12 scores (2.4 ± 3.5 vs. 1.8 ± 3.4, p = 0.030), Mig-SCog scores (9.3 ± 4.7 vs. 8 ± 4.9, p = 0.004), and GAD-7 scores (6.9 ± 5.1 vs. 6.2 ± 5.4, p = 0.039), and were more likely to have a migraine diagnosis (335/350 [95.7%] vs. 192/215 [89.3%], p = 0.003). CONCLUSIONS: Those with headaches prior to TBI are less likely to receive a diagnosis of PTH. They have more severe symptoms of cutaneous allodynia, cognitive impairment, and generalized anxiety. This analysis suggests that pre-TBI headaches might impact post-TBI headache diagnoses and associated features.

Chronic versus episodic migraine: The 15-day threshold does not adequately reflect substantial differences in disability across the full spectrum of headache frequency.

OBJECTIVE: To evaluate whether the 15-day threshold of headache days per month adequately reflects substantial differences in disability across the full spectrum of migraine. BACKGROUND: The monthly frequency of headache days defines migraine subtypes and has crucial implications for epidemiological and clinical research as well as access to care. METHODS: The patients with migraine (N = 836) who participated in the American Registry for Migraine Research, which is a multicenter, longitudinal patient registry, between February 2016 and March 2020, were divided into four groups based on monthly headache frequency: Group 1 (0-7 headache days/month, n = 286), Group 2 (8-14 headache days/month, n = 180), Group 3 (15-23 headache days/month, n = 153), Group 4 (≥24 headache days/month, n = 217). Disability (MIDAS), Pain intensity (NRS), Work Productivity and Activity Impairment (WPAI), Pain Interference (PROMIS-PI), Patient Health Questionnaire-4 (PHQ-4), and General Anxiety Disorder-7 (GAD-7) scores were compared. RESULTS: Mean (standard deviation [SD]) age was 46 (13) years (87.9% [735/836] female). The proportion of patients in each group was as follows: Group 1 (34.2% [286/836]), Group 2 (21.5% [180/836]), Group 3 (18.3% [153/836]), and Group 4 (26.0% [217/836]). There were significant relationships with increasing disability, lost productive time, and pain interference in higher headache frequency categories. There were no significant differences between Group 2 and Group 3 for most measures (NRS, all WPAI scores, PROMIS-PI, GAD-7, and PHQ-4), although MIDAS scores differed (median [interquartile range (IQR)]; 38 [20-58] vs. 55 [30-90], p < 0.001). Patients in Group 1 had significantly lower MIDAS (median [IQR];16 [7-30], p < 0.001), WPAI-% total active impairment (mean (SD): Group 1 [30.9 (26.8)] vs. Group 2 [39.2 (24.5), p = 0.017], vs. Group 3 [45.9 (24.1), p < 0.001], vs. Group 4 [55.3 (23.0), p < 0.001], and PROMIS-PI-T score (Group 1 [60.3 (7.3)] vs. Group 2 [62.6 (6.4), p = 0.008], vs. Group 3 [64.6 (5.6), p < 0.001], vs. Group 4 [66.8 (5.9), p < 0.001]) compared to all other groups. Patients in Group 4 had significantly higher MIDAS (median (IQR): Group 4 [90 (52-138)] vs. Group 1 [16 (7-30), p < 0.001], vs. Group 2 [38 (20-58), p < 0.001], vs. Group 3 [55 (30-90), p < 0.001], WPAI-%Presenteeism (Group 4 [50.4 (24.4)] vs. Group 1 [28.8 (24.9), p < 0.001], vs. Group 2 [34.9 (22.3), p < 0.001], vs. Group 3 [40.9 (22.3), p = 0.048], WPAI-% total work productivity impairment (Group 4 [55.9 (26.1)] vs. Group 1 [32.1 (37.6), p < 0.001], vs. Group 2 [38.3 (24.0), p < 0.001], vs. Group 3 [44.6 (24.4), p = 0.019]), and WPAI-%Total activity impairment (Group 4 [55.3 (23.0)] vs. Group 1 [30.9 (26.8), p < 0.001], vs. Group 2 [39.2 (24.5), p < 0.001], vs. Group 3 [45.9 (24.1), p = 0.025]) scores compared with all other groups. CONCLUSION: Our data suggest that the use of a 15 headache day/month threshold to distinguish episodic and chronic migraine does not capture the burden of illness nor reflect the treatment needs of patients. These results have important implications for future refinements in the classification of migraine.

Mild traumatic brain injury affects the features of migraine.

BACKGROUND: Headache is one of the most common symptoms after concussion, and mild traumatic brain injury (mTBI) is a risk factor for chronic migraine (CM). However, there remains a paucity of data regarding the impact of mTBI on migraine-related symptoms and clinical course. METHODS: Of 2161 migraine patients who participated in the American Registry for Migraine Research between February 2016 and March 2020, 1098 completed questions assessing history of TBI (50.8%). Forty-four patients reported a history of moderate to severe TBI, 413 patients reported a history of mTBI. Patients' demographics, headache symptoms and triggers, history of physical abuse, allodynia symptoms (ASC-12), migraine disability (MIDAS), depression (PHQ-2), and anxiety (GAD-7) were compared between migraine groups with (n = 413) and without (n = 641) a history of mTBI. Either the chi-square-test or Fisher's exact test, as appropriate, was used for the analyses of categorical variables. The Mann-Whitney test was used for the analyses of continuous variables. Logistic regression models were used to compare variables of interest while adjusting for age, gender, and CM. RESULTS: A significantly higher proportion of patients with mTBI had CM (74.3% [307/413] vs. 65.8% [422/641], P = 0.004), had never been married or were divorced (36.6% [147/402] vs. 29.4% [187/636], P = 0.007), self-reported a history of physical abuse (24.3% [84/345] vs. 14.3% [70/491], P <  0.001), had mild to severe anxiety (50.5% [205/406] vs. 41.0% [258/630], P = 0.003), had headache-related vertigo (23.0% [95/413] vs. 15.9% [102/640], P = 0.009), and difficulty finding words (43.0% [174/405] vs. 32.9% [208/633], P <  0.001) in more than half their attacks, and headaches triggered by lack of sleep (39.4% [155/393] vs. 32.6% [198/607], P = 0.018) and reading (6.6% [26/393] vs. 3.0% [18/607], P = 0.016), compared to patients without mTBI. Patients with mTBI had significantly greater ASC-12 scores (median [interquartile range]; 5 [1-9] vs. 4 [1-7], P < 0.001), MIDAS scores (42 [18-85] vs. 34.5 [15-72], P = 0.034), and PHQ-2 scores (1 [0-2] vs. 1 [0-2], P = 0.012). CONCLUSION: Patients with a history of mTBI are more likely to have a self-reported a history of physical abuse, vertigo, and allodynia during headache attacks, headaches triggered by lack of sleep and reading, greater headache burden and headache disability, and symptoms of anxiety and depression. This study suggests that a history of mTBI is associated with the phenotype, burden, clinical course, and associated comorbid diseases in patients with migraine, and highlights the importance of inquiring about a lifetime history of mTBI in patients being evaluated for migraine.

Case Report: Shortest Course of Pediatric Paroxysmal Hemicrania.

Paroxysmal hemicrania (PH) is a rare primary headache disorder, especially among children. We describe herein a case with the shortest course of pediatric PH among previously reported cases, and the first case report of Japanese pediatric PH. An 11-year-old boy was referred to our clinic by his primary care physician for a headache evaluation. He had been complaining of severe, sharp, pulsating headache for 5 days. Attacks were restricted to the left side with a duration ranging from 2 to 20 minutes, 20-30 times a day. Attacks were associated with left autonomic symptoms (conjunctival injection, lacrimation, nasal congestion, eyelid edema, and ptosis). Two days after we prescribed indomethacin at 0.9 mg/kg/day, the patient was headache free. He stopped taking indomethacin 14 days after consultation because of drug eruptions. As of the time of writing, more than 1 year later, he has experienced no recurrence of headache. This case indicates the importance of improving awareness among general doctors regarding PH in children, and of conducting further investigations about low-dose, short-term indomethacin treatment.

Myasthenic symptoms in anti-low-density lipoprotein receptor-related protein 4 antibody-seropositive amyotrophic lateral sclerosis: two case reports.

BACKGROUND: Myasthenic symptoms can be present in patients with amyotrophic lateral sclerosis (ALS). These symptoms have been considered to be caused by the degeneration of distal motor neurons and the neuromuscular junction (NMJ). Recent studies suggested that antibody to low-density lipoprotein receptor-related protein 4 (LRP4) was a pathogenic agent of myasthenia gravis (MG), and it was also detected in ALS patients. CASE PRESENTATION: Patient 1: A 58-year-old Japanese man developed progressive weakness and subsequent myasthenic symptoms including oculomotor disturbance. Clinical examination and electrophysiological studies confirmed upper and lower motor neuron involvement and NMJ dysfunction, and anti-LRP4 antibody was detected in his serum. A series of immunotherapies, including steroid pulse therapy, intravenous immunoglobulin, and plasmapheresis, was performed, and the myasthenic symptoms partially improved. The titer of anti-LRP4 antibody subsequently decreased. However, the therapeutic effect was transient, and ALS symptoms progressed. His clinical findings fulfilled the criteria of probable ALS using the Awaji criteria. Patient 2: A 74-year-old Japanese man suffered from progressive weakness of all limbs and dropped head in the evening. He complained of diplopia with a lateral horizontal gaze. Probable ALS was diagnosed because of the upper and lower motor neuron signs, whereas anti-LRP4 antibody was detected. Several immunotherapies were administered, and the myasthenic symptoms partially responded to each therapy. However, the truncal muscle weakness progressed, and he died of respiratory failure. CONCLUSION: We report two anti-LRP4 antibody-seropositive ALS patients with myasthenia who were not typical of ALS patients, and showed partial responses to immunotherapies. The anti-LRP4 antibody-seropositive status may influence developing ALS and cause additional ALS symptoms.

Quality of life and work productivity and activity impairment among online survey respondents with migraine across a range of headache frequency.

Objective: This study aimed to describe the migraine burden and healthcare utilization in the context of headache frequency using nationwide claims data linked to online survey data previously collected in Japan. Background: It has been shown that increase in headache frequency can impose greater impact on individuals' daily and social functioning, but migraine burden in those with low-frequency headaches remains largely unknown in Japan. Methods: This post-hoc, observational study reported on 674 respondents who were working individuals and their family members aged 19-74 years, responded to an online questionnaire (response rate: 14.1% [21,704 responded/153,545 kencomⓇ registrants]), and were previously classified as having migraine. Disease burden in terms of Migraine-Specific Quality of Life (MSQ) and Work Productivity and Activity Impairment (WPAI) was compared across 0-3, 4-7, 8-14, and ≥ 15 monthly headache days (MHD). Results: Among 674 respondents, 419 (62.2%), 148 (22.0%), 61 (9.1%), and 46 (6.8%) had 0-3, 4-7, 8-14, and ≥ 15 MHD, respectively. Of those, 55 (13.1%), 31 (20.9%), 19 (31.1%), and 20 (43.5%) respondents consulted physicians for headaches. Moderate-to-severe impairments in daily activities were reported by 298 (71.1%), 110 (74.3%), 46 (75.4%), and 38 (82.6%) respondents. The proportion of the respondents with WPAI >0% generally increased with increasing headache frequency (presenteeism: 41.7 and 67.5% in respondents with 0-3 and ≥ 15 MHD, respectively; overall work impairment: 44.8 and 72.5%, respectively; and activity impairment: 44.9 and 73.9%, respectively), except for absenteeism (12.4 and 22.5%, respectively). The mean MSQ score declined with increasing MHD (Role function-restrictive: 75.1 and 59.5 in those with 0-3 and ≥ 15 MHD, respectively; Role function-preventive: 85.8 and 75.0, respectively; and Emotional function: 81.9 and 63.6, respectively). Conclusion: Based on the Japanese nationwide claims data, quality of life and work productivity decreased with increasing numbers of headache days. Substantial disease burden paired with low levels of healthcare utilization highlights the need for medical or non-medical intervention.

Zinc Administration Favorably Affects Prophylactic Therapy-refractory Migraine Attacks: A Case Series.

Notably, certain nutrients are effective in preventing migraine. Nonetheless, zinc replacement therapy for migraine treatment has yet to be explored. We herein report four patients with migraine who were refractory to prophylactic therapy and whose headache frequency and severity improved with zinc supplementation. Zinc administration may be an option for treating patients with prophylaxis-refractory migraine. Further investigation is required to determine the efficacy of zinc replacement therapy as a treatment option for migraine.

Recurrence of intracranial artery dissection more than a half year after the initial event.

INTRODUCTION: The management of intracranial artery dissection (IAD) has not been established, partly because the long-term course of the disease is not well-known. We retrospectively investigated the long-term course of IAD without subarachnoid hemorrhage (SAH) as an initial clinical presentation. METHODS: Of 147 consecutive spontaneous first-ever IAD patients hospitalized between March 2011 and July 2018, 44 with SAH were excluded, and the remaining 103 were investigated. We divided the patients into two groups: Recurrence group as those with recurrent intracranial dissection >1 month after the initial dissection, and Non-recurrence group as those without them. Clinical characteristics were compared between those two groups. RESULTS: The mean follow-up period was 33 months from the initial event. Recurrent dissection occurred in 4 patients (3.9%) >7 months after the initial dissection, none of whom were on antithrombotic treatments at recurrence. Three had ischemic stroke and the other had local symptoms [range: 8 to 44 months]. Nine (8.7%) had an ischemic stroke within 1 month of the initial event. There was no recurrent dissection between 1 and 7 months after the initial event. There was no significant difference in baseline characteristics between Recurrence and Non-recurrence groups. CONCLUSIONS: Four out of the 103 (3.9%) IAD patients had recurrent IAD >7 months after the initial event. IAD patients should be followed up for more than a half year after the initial event, with consideration given to the recurrence of IAD. Further research is needed on recurrence prevention measures to IAD patients.

A combined treatment for acute larger lacunar-type infarction.

Larger lacunar-type infarcts (LLIs), presumably caused by occlusion at the orifices or proximal portions of larger-caliber penetrating arteries by atheromatous plaque, are frequently associated with progressive motor deficits (PMD) and lead to poor functional outcome. This study was conducted to examine the efficacy of a combined treatment to prevent PMD or improve the functional outcome in patients with LLI. A total of 218 consecutive patients with LLI and motor lacunar syndrome were enrolled, including 138 patients with infarcts in the territory of the lenticulostriate artery and anterior choroidal artery (supratentrial group) and 80 patients with infarcts in the territory of the anterior pontine artery (pontine group). The prevalence of PMD and functional outcome represented by modified Rankin Scale (mRS) score at 1 month after ictus were compared between groups treated with a combined treatment approach consisting of cilostazol and edaravone (n = 100) and a conventional treatment approach (n = 118). The efficacy of the combined treatment provided in 2005-2009 was compared with conventional treatment provided in 2001-2005. There was no significant difference in the prevalence of PMD between the 2 treatment groups. The combined treatment group had significantly more favorable outcomes compared with the conventional treatment group in the total population (P = .0078, Wilcoxon Mann-Whitney test) and in the pontine group (P = .0042). Logistic regression analysis showed that an initial National Institutes of Health Stroke Scale score <4, the absence of PMD, and the novel combined treatment approach were independently associated with favorable functional outcome. The novel combined treatment approach was safe and effective in improving functional outcome in acute LLI, but not effective in preventing PMD.

Possible roles for phytohormones in controlling the stomatal behavior of Mesembryanthemum crystallinum during the salt-induced transition from C3 to crassulacean acid metabolism.

The halophyte ice plant (Mesembryanthemum crystallinum) converts its mode of photosynthesis from C3 to crassulacean acid metabolism (CAM) during severe water stress. During the transition to CAM, the plant induces CAM-related genes and changes its diurnal stomatal behavior to take up CO2 efficiently at night. However, limited information concerning this signaling exists. Here, we investigated the changes in the diurnal stomatal behavior of M. crystallinum during its shift in photosynthesis using a detached epidermis. M. crystallinum plants grown under C3 conditions opened their stomata during the day and closed them at night. However, CAM-induced plants closed their stomata during the day and opened them at night. Quantitative analysis of endogenous phytohormones revealed that trans-zeatin levels were high in CAM-induced plants. In contrast, the levels of jasmonic acid (JA) and JA-isoleucine were severely reduced in CAM-induced plants, specifically at night. CAM induction did not alter the levels of abscisic acid; however, inhibitors of abscisic acid synthesis suppressed CAM-induced stomatal closure. These results indicate that M. crystallinum regulates the diurnal balance of cytokinin and JA during CAM transition to alter stomatal behavior.

Childhood-onset multifocal motor neuropathy with IgM antibodies to GM2 and GalNac-GD1a.

BACKGROUND: Multifocal motor neuropathy (MMN) is an acquired immune-mediated form of neuropathy characterized by upper and asymmetric limb weakness without sensory loss. The mean age of onset is 40 years (range, 20-70 years), and childhood-onset MMN is extremely rare. In the present report, we discuss a case of childhood-onset MMN in a patient who tested positive for anti-GM2 and anti-GalNac-GD1a immunoglobulin M (IgM) antibodies. CASE REPORT: A 12-year-old girl presented with progressive weakness of the upper extremities without sensory loss. Electrophysiological assessments revealed definite conduction blocks in the left median and bilateral radial nerves. She was diagnosed with MMN in accordance with the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria. Serological studies revealed that she tested positive for IgM antibodies to GM2 and GalNac-GD1a. Partial improvements in both muscle weakness and electrophysiological assessments were achieved after 8 months of high-dose intravenous immunoglobulin (IVIg) treatment. CONCLUSION: Although childhood-onset MMN is rare, most patients respond to IVIg treatment. This is the first case of childhood-onset MMN in a patient who tested positive for anti-GM2 and anti-GalNac-GD1a IgM antibodies. Although half of the adult patients with MMN test positive for anti-GM1 IgM antibodies, they were not detected in our patient. Comprehensive testing for serum anti-glycolipid antibodies in addition to GM1 may aid in the diagnosis of childhood-onset MMN.

Effect of Migraine on Pregnancy Planning: Insights From the American Registry for Migraine Research.

OBJECTIVE: To evaluate the effect of migraine on women's pregnancy plans. PATIENTS AND METHODS: Participants were enrolled in the American Registry for Migraine Research, an observational study that recruits patients from headache specialty clinics across the United States. Data for this analysis were collected via patient-completed questionnaires completed from February 1, 2016, through September 23, 2019. Participants were adult women with migraine who answered the American Registry for Migraine Research family planning questions. RESULTS: Of 607 women, 19.9% (n=121) avoided pregnancy because of migraine. Compared with women who did not avoid pregnancy, those who did were younger (37.5±9.2 years vs 47.2±13.3 years; P<.001), had fewer children (0.8±1.1 vs 1.5±1.5; P<.001), and were more likely to have chronic migraine (n=99 [81.8%] vs n=341 [70.2%]; P=.012) and menstrually associated migraine (n=5 [4.1%] vs n=5[1.0%]; P=.031). Women who avoided pregnancy believed that their migraine would be worse during pregnancy (n=87[72.5%]), disability caused by migraine would make pregnancy difficult (n=82[68.3%]), the migraine medications they take would negatively affect their child's development (n=92[76.0%]), and migraine would cause the baby to have abnormalities at birth (n=17[14.0%]). CONCLUSION: Migraine effects pregnancy plans of many women, especially of those who are younger and have menstrual migraine and chronic migraine. Women who avoid pregnancy because of migraine believe that migraine will worsen during pregnancy, make their pregnancy difficult, and have negative effects on their child. Study results highlight the importance of educating women with migraine about the relationships between migraine and pregnancy so that informed family planning decisions can be made.

[CSF normocytosis in meningitis due to primary infection of human immunodeficiency virus].

A 32-year-old homosexual man was admitted because of acute headache, fever, and lymphoadenopathy. The neurological examination revealed nuchal rigidity and positive Kernig's sign. The cell count of cerebrospinal fluid (CSF) at the time of admission, however, was four per microliter and subsequently increased up to 31 per microliter in three days. The serum antibody for human immunodeficiency virus (HIV) was positive in ELISA and the cell number of CD4 positive population decreased to 280. The RT-PCR for HIV RNA was 7.6 x 10(5) copies per milliliter, which gradually decreased, leading to the diagnosis of meningitis due to HIV itself. The Western blotting for HIV antibodies were positive for p24, p40 and p55, whereas that for gp 41 was negative in serum and CSF, suggesting that the meningitis occurred during the seroconversion in this patient. We surmise that aseptic meningitis during HIV primary infection usually results in mild CSF pleocytosis and sometimes leads to even normocytosis shown as in this patient, probably because cellular immunity is temporally suppressed in acute HIV infection.

Biomarker repurposing: Therapeutic drug monitoring of serum theophylline offers a potential diagnostic biomarker of Parkinson's disease.

Caffeine has been considered a neuroprotective agent against Parkinson's disease (PD). Recent metabolomic analysis showed that levels of caffeine and its metabolites were decreased in sera from patients with PD compared with those from healthy controls. We focused on theophylline, which is one of the primary caffeine metabolites, as a candidate biomarker of PD because: (1) its serum level can be measured in hospital laboratories by standardized immunoassay kits for therapeutic drug monitoring and (2) because it is less markedly affected by caffeine intake. This was a pilot study to measure the levels of theophylline in sera of 31 patients with PD and 33 age-matched disease controls using an immunoassay kit. We confirmed the previous finding of significantly lower levels of serum theophylline in the PD group compared with control group (PD: 0.07±0.09 µg/mL, control: 0.18±0.24 µg/mL, p<0.05). Using such an approach of applying known medical biomarkers for neurodegenerative diseases may allow us to skip the process from the discovery phase to clinical application, and subsequently shorten the period of time necessary for biomarker development.

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS).

Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a novel ataxic disorder consisting of the triad of cerebellar impairment, bilateral vestibular hypofunction, and a somatosensory deficit. We report the first Japanese case of CANVAS. The patient is a 68-year-old Japanese male. He was referred to our university for further evaluation of progressive gait disturbance and ataxia. He exhibited horizontal gaze-evoked nystagmus and sensory deficit. Nerve conduction studies showed sensory neuronopathy. Magnetic resonance imaging showed the atrophy of vermis but not of the brainstem. The caloric stimulation and video head impulse test (vHIT) showed bilateral vestibulopathy. The visually enhanced vestibulo-ocular reflex (VVOR) was also impaired. In addition to neurological and electrophysiological examinations, simple neuro-otological examinations (i.e., caloric stimulation, vHIT, and VVOR) may reveal more non-Caucasian cases.

A case of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) with the largest lesion in the temporal lobe.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory disease of the central nervous system with a predilection for the hindbrain. Generally, lesions decrease in size with increasing distance from the hindbrain. We herein describe a case of CLIPPERS in a patient showing the largest lesions in the temporal lobe. A 49-year-old man consulted to our hospital with a 22-day history of a high fever and an abnormal visual field involving the left eye. Brain MRI showed a FLAIR hyperintense lesion in the right temporal lobe with punctate gadolinium enhancement. Several days later, lesions showing similar enhancement extended to the pons, medulla oblongata, and cerebellar hemispheres. Biopsy of the right temporal lobe lesion revealed perivascular lymphocytic infiltrates without any findings of demyelination, lymphoma, or glioma. He was diagnosed with CLIPPERS based on clinical, radiological, and histopathological findings. Clinical and radiological findings improved quickly after steroid therapy. CLIPPERS could represent larger lesions distant from the hindbrain showing punctate enhancement.

Development of a Biochemical Diagnosis of Parkinson Disease by Detection of α-Synuclein Misfolded Aggregates in Cerebrospinal Fluid.

IMPORTANCE: Parkinson disease (PD) is a highly prevalent and incurable neurodegenerative disease associated with the accumulation of misfolded α-synuclein (αSyn) aggregates. An important problem in this disease is the lack of a sensitive, specific, and noninvasive biochemical diagnosis to help in clinical evaluation, monitoring of disease progression, and early differential diagnosis from related neurodegenerative diseases. OBJECTIVE: To develop a novel assay with high sensitivity and specificity to detect small quantities of αSyn aggregates circulating in cerebrospinal fluid (CSF) of patients affected by PD and related synucleinopathies. DESIGN, SETTING, AND PARTICIPANTS: The strategy evaluated in this proof-of-concept study uses the protein misfolding cyclic amplification (PMCA) technology that detects minute amounts of misfolded oligomers by taking advantage of their ability to nucleate further aggregation, enabling a very high amplification of the signal. The technology was first adapted with synthetic αSyn oligomers prepared in vitro and used to screen in 2 blinded cohorts of CSF samples from German and Japanese patients with PD (n = 76) and individuals serving as controls affected by other neurologic disorders (n = 65), neurodegenerative diseases (n = 18), and Alzheimer disease (n = 14). The kinetics of αSyn aggregation were measured by αSyn-PMCA in the presence of CSF samples from the participants to detect αSyn oligomeric seeds present in this biological fluid. The assays were conducted from November 15, 2013, to August 28, 2015. MAIN OUTCOMES AND MEASURES: Kinetic parameters correlated with disease severity at the time of sample collection, measured by the Hoehn and Yahr scale, with the lowest grade indicating unilateral involvement with minimal or no functional impairment, and the highest grade defining patients with complete confinement to wheelchair or bed. RESULTS: Studies with synthetic αSyn aggregates showed that αSyn-PMCA enabled to detect as little as 0.1 pg/mL of αSyn oligomers. The αSyn-PMCA signal was directly proportional to the amount of αSyn oligomers added to the reaction. A blinded study of CSF samples correctly identified patients affected by PD with an overall sensitivity of 88.5% (95% CI, 79.2%-94.6%) and specificity of 96.9% (95% CI, 89.3%-99.6%). The αSyn-PMCA results for different patients correlated with the severity of the clinical symptoms of PD (Japanese cohort: rs = -0.54, P = .006; German cohort: rs = -0.36, P = .02). CONCLUSIONS AND RELEVANCE: The findings suggest that detection of αSyn oligomers by αSyn-PMCA in the CSF of patients affected by PD may offer a good opportunity for a sensitive and specific biochemical diagnosis of the disease. Further studies are needed to investigate the usefulness of αSyn-PMCA to monitor disease progression and for preclinical identification of patients who may develop PD.