Clinical Evaluation After Discontinuation of Galcanezumab in Japanese Patients with Episodic and Chronic Migraine: Analysis of a Randomized, Placebo-Controlled Trial and Open-label Extension Study.

INTRODUCTION: This analysis of two Japanese clinical trials evaluated efficacy and safety after galcanezumab (GMB) discontinuation in patients with episodic migraine (EM) and chronic migraine (CM). METHODS: Data were from a 6-month, randomized, double-blind, placebo [PBO]-controlled primary trial (patients with EM) and a 12-month open-label extension trial (patients with EM/CM). Patients received 6 months' (primary) or 12/18 months' (extension) treatment with GMB 120 mg (GMB120) plus 240-mg loading dose or 240 mg (GMB240) with 4 months' post-treatment follow-up. Efficacy was assessed as number of monthly migraine headache days during post-treatment. Safety was assessed via post-treatment-emergent adverse events (PTEAEs). RESULTS: The analysis population included 186 patients from the primary trial (PBO N = 93; GMB120 N = 45; GMB240 N = 48), 220 patients with EM from the extension trial (PBO/GMB120 N = 57; PBO/GMB240 N = 55; GMB120/GMB120 N = 55; GMB240/GMB240 N = 53), and 55 patients with CM (GMB120 N = 28; GMB240 N = 27). In patients with EM receiving 6 months' GMB120, mean standard deviation (SD) monthly migraine headache days increased from 5.69 (4.64) at treatment end to 6.24 (4.37) at end of follow-up but did not return to pre-treatment levels (8.80 [2.96]). In the extension trial, mean monthly migraine headache days in patients with EM receiving GMB120 were 4.13 (3.85) after 12 months and 4.45 (3.78) at end of follow-up, and 3.59 (3.48) after 18 months and 3.91 (3.57) at end of follow-up. Monthly migraine headache days in patients with CM (12 months' GMB120) were 10.71 (4.61) at treatment end and 11.17 (5.64) at end of follow-up (pre-treatment 20.15 [4.65]). Similar results were seen for patients receiving GMB240. The most observed PTEAE after GMB discontinuation was nasopharyngitis. CONCLUSION: Galcanezumab exhibited post-treatment efficacy for up to 4 months in Japanese patients with EM and with CM. No unexpected safety signals were observed. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02959177 and NCT02959190.

Decreased stimulus-driven connectivity of the primary visual cortex during visual motion stimulation in amnestic mild cognitive impairment: An fMRI study.

Motion perceptual deficits are common in Alzheimer's disease (AD). Although the posterior parietal cortex is thought to play a critical role in these deficits, it is currently unclear whether the primary visual cortex (V1) contributes to these deficits in AD. To elucidate this issue, we investigated the net activity or connectivity within V1 in 17 amnestic mild cognitive impairment (aMCI) patients, 17 AD patients and 17 normal controls (NC) using functional magnetic resonance imaging (fMRI). fMRI was recorded under two conditions: visual motion stimulation and resting-state. The net activity or connectivity within V1 extracted by independent component analysis (ICA) was significantly increased during visual motion stimuli compared with that of the resting-state condition in NC, but not in aMCI or AD patients. These findings suggest the alteration of the net activity or connectivity within V1, which may contribute to the previously reported motion perceptual deficits in aMCI and AD. Therefore, the decreased net V1 activity measured as the strength of the ICA component may provide a new disease biomarker for early detection of AD.

Analysis of cerebral lobar microbleeds and a decreased cerebral blood flow in a memory clinic setting.

OBJECTIVE: Cerebral microbleeds (MBs) have been previously associated with cognitive dysfunction, including Alzheimer's disease. In the present study, we aimed to clarify the relationship between cerebral lobar MBs and the regional cerebral blood flow (CBF). METHODS: We investigated the data obtained from 122 patients in our memory clinic who were examined by both MRI and (99m)Tc-ethyl cysteinate dimer (ECD)-single photon emission computed tomography (SPECT). Patient brain scans were superimposed and brain regions containing both decreased CBF and MBs were visually identified. For each patient eight brain regions were evaluated, comprising the right and left frontal, temporal, parietal, and occipital lobes. RESULTS: Cerebral MBs were detected in 36 of the 122 (29.5%) patients. Of these 36 patients, 23 had detectable lobar MBs, which were primarily distributed in the occipital lobe in 19 of the 46 (41.3%) regions with lobar MBs. The frequency of MBs accompanied by a decreased CBF in the parietal and occipital lobes was significantly higher than that observed in the frontal lobe (73.3% vs. 27.3%, p<0.05, and 73.7% vs. 27.3%, p<0.05, respectively). Additionally, a decreased CBF was observed significantly more frequently in the brain regions with 5 or more MBs compared to the regions with one microbleed (83.3 vs. 25.0%, p<0.0005). Among the 17 patients with observable MBs accompanied by a decreased CBF, none were initially diagnosed with either subjective complaints or mild cognitive impairment. CONCLUSION: We determined that the cerebral lobar MBs located in the parietal and occipital lobes, and the lobar regions with a large number of MBs, were significantly more likely to be accompanied by a decreased CBF.

[A case of acute autonomic, sensory and motor neuropathy with swelling and gadolinium enhancement of bilateral trigeminal nerve on MRI and dissociation between superficial and deep sensation disturbance].

We report a case of a 46-year old man with acute autonomic, sensory and motor neuropathy (AASMN). He developed severe orthostatic hypotension, anuria,anhydrosis, tonic pupil with dysarthria, dysphagia, jaw claudication, and dysesthesia and sharp pain several days after symptom of upper respiratory infection. Neurological examination revealed severely decreased superficial sensation with normal deep sensation. Brain MRI findings showed bilateral trigeminal nerve swelling with gadolinium (Gd) enhancement. His motor and sensory symptoms and MRI abnormality were improved after the administration of intravenous immunoglobulin and intravenous methylprednisolone therapy; however his autonomic symptoms scarcely reacted to these immunotherapies. As long as we investigated in AASMN cases, bilateral trigeminal nerve swelling with Gd enhancement and dissociation between superficial and deep sensation disturbance have not reported, suggesting that the present case mainly disrupted C nerve fibers distributing postganglionic autonomic and temperature-pain sensory nerves.

[Migraine with aura and recurrent vertigo attacks in a patient with hereditary hemorrhagic telangiectasia].

Hereditary hemorrhagic telangiectasia (HHT) is characterized by systemic vascular diseases mainly shown as arterio-visnous fistula (AVF). Here, we presented a 29-year-old woman with HHT complicated with migraine with aura (MWA) and vertigo. At the age of twelve years, she developed migraine with visual aura. At that time, migraine attacks were seen three times a year. At the age of 29 years, she also developed speech disturbance as migraine aura. At the ages of 20 and 29 years, she repeatedly suffered from positional vertigo attacks for a month. Physical examination revealed dilation of the capillary vessels at tongue, soft palate, and nasal mucosa and AVFs were located in the upper cervical cord, parietal lobe, and bilateral lungs. These clinical findings were consistent with the diagnostic criteria of HHT. Embolization of pulmonary AVF decreased the frequency of migraine attacks during 2-year follow-up after the embolization. The frequency of migraine in patients with HHT is higher than that of general population as well as the prevalence of vertigo. Therefore, MWA and vertigo presented in the patient with HHT suggests that there is a common pathological mechanism of dysfunction of endothelial cells and R-L shunt, among HHT, MWA, and vertigo.

Frostbite-like skin lesion as an autonomic symptom of Isaacs' syndrome.

A 25-year-old woman complained of numbness of the extremities, following muscle rigidity and tenderness. The presence of anti-voltage-gated potassium channel antibody led to the diagnosis of Isaacs' syndrome. Twenty-seven months after the first symptom, she developed a pricking pain sensation in the lateral left foot, and then gradually developed a purple skin lesion resembling frostbite. The lesion completely disappeared 2 days later. An incidental episode occurred at the same site 8 months later. Frostbite-like skin lesions may be a rare autonomic manifestation in Isaacs' syndrome.

[Sporadic hemiplegic migraine-like headache in a patient with systemic lupus erythematosus].

A 39-year-old woman suddenly developed numbness of the left arm following mild weakness of the left upper and lower extremities, blindness in the left visual field, and difficulty finding words. Her symptoms lasted for two hours with no deficit remaining. Six months after the first episode, the first of several more occurred. Two of the episodes were followed by nausea and a non-pulsative headache around the left temporo-parietal regions and the orbit. She had also been suffering recurrent skin eruptions for the previous two years. There was no family history of migraine. Her neurological symptoms fulfilled the criteria of sporadic hemiplegic migraine (SHM). Biopsy of skin eruption revealed lymphocytic infiltration and liquefied degeneration of basal lamina. These findings were compatible with systemic lupus erythematosus (SLE). There were no lesions evident on brain MR. We diagnosed SLE and after administration of aspirin (100 mg/day) and lomerizine hydrochloride (10 mg/day), her neurological symptom completely disappeared. SHM-like headache in patients with SLE is extremely rare. Although an autoimmune or thrombotic mechanism has been suggested for neurological symptoms in SLE, further studies are needed to elucidate the mechanism. We propose that SLE should be considered as one of the differential diagnoses of SHM.

[A case of immune-mediated encephalopathy showing refractory epilepsy and extensive brain MRI lesions associated with anti-glutamic acid decarboxylase antibody].

We reported a patient with immune-mediated encephalopathy showing refractory epilepsy and multiple brain lesions on MRI. The patient had high titers of anti-glutamic acid decarboxylase (GAD) antibody in sera and cerebrospinal fluid (CSF). A 36-year-old previously healthy woman was admitted to our hospital with onset of sudden generalized seizure that then persisted for one month. She had repeated epileptic attacks accompanied with loss of consciousness, and was refractory to valproic acid, zonisamide (200 mg/day) and phenobarbital (200 mg/day). Brain MRI showed multiple hyperintense lesions in predominantly bilateral frontal lobes, parietal lobes, occipital lobes and cingulate cortices. EEG showed epileptic activities (frequent sharp waves) in bilateral frontal regions. After admission, attacks disappeared through the administration of clonazepam (1.5 mg/day), though the patient remained slightly disoriented. As titers of anti-GAD antibody in sera and CSF were extremely high, we implemented plasma exchanges. After treatment, titers of anti-GAD antibody in sera and CSF decreased. The patient completely recovered to an alert state and the abnormal MRI lesions almost disappeared. Since GAD catalyzes production of gamma-aminobutyric acid (GABA), it is proposed that anti-GAD antibodies reduce synthesis of GABA or interferes with exocytosis of GABA in the nervous system. Anti-GAD antibodies are detected in some rare neurological disorders such as stiff-person syndrome. Recently, anti-GAD antibodies have been reported as implicated in cerebellar ataxia, palatal myoclonus, refractory epilepsy and limbic encephalitis. Epilepsy associated with the anti-GAD antibody is mostly pharmacoresistant temporal lobe epilepsy; with brain MRI showing no abnormality or only hippocampal sclerosis. It is very rare that brain MRI shows extensive abnormal lesions except in the hippocampus. This case suggests that anti-GAD antibodies could contribute to unexplained encephalopathy with extensive brain MRI lesions and drug-resistant symptomatic epilepsy.

Reappraisal of brain MRI features in patients with multiple sclerosis and neuromyelitis optica according to anti-aquaporin-4 antibody status.

Brain lesions are not uncommon in neuromyelitis optica (NMO) patients with anti-aquaporin-4 (AQP4) antibody; however, the appearance of these lesions is said to be different from that of those in Western patients with multiple sclerosis (MS). To clarify the similarities and dissimilarities of brain lesions in anti-AQP4 antibody-positive and -negative MS and NMO patients, we examined the presence of anti-AQP4 antibody in the sera of 148 consecutive patients fulfilling Poser's criteria for clinically definite MS, of whom 38 also met the revised NMO criteria, using an immunofluorescence method, and analyzed brain lesions by magnetic resonance imaging (MRI). Brain lesions fulfilling the Barkhof criteria were significantly more common in 121 patients without anti-AQP4 antibody than in 27 patients with anti-AQP4 antibody (57.0% vs. 33.3%, P=0.033), while the frequency of those that met the Paty criteria was not different between the two groups (74.4% vs. 73.5%). Ovoid lesions were detected more commonly in patients without anti-AQP4 antibody than in those with the antibody (72.3% vs. 48.2%, P=0.022). The anti-AQP4 antibody-positive patients had significantly more atypical brain lesions, such as extensive brain lesions, than the anti-AQP4 antibody-negative ones (18.5% vs. 1.7%, P=0.0023). Thus, although MS-like brain lesions are more common in anti-AQP4 antibody-negative patients than anti-AQP4 antibody-positive patients, approximately 30 to 50% of patients with anti-AQP4 antibody harbour brain MRI lesions indistinguishable from those present in typical MS patients, such as periventricular ovoid lesions, suggesting the existence of considerable overlap in brain MRI features between anti-AQP4 antibody-positive and -negative Asian patients. In the present study, NMO patients with brain lesions showed a significantly higher annualized relapse rate (P(corr)=0.017) and higher frequency of anti-AQP4 antibody (P(corr)<0.0001) than typical NMO patients without brain lesions, suggesting that development of brain lesions in NMO may reflect high disease activity and thus be a warning sign.

[Predominant parasympathetic involvement in a patient with Charcot-Marie-Tooth disease caused by the MPZ Thr124Met mutation].

Erectile dysfunction, dysuria, photophobia, and chronic cough developed insidiously in a 49-year-old man from his third decade. Severe difficulty of urination resulted in intermittent catheterization. He had six family members who had suffered similar autonomic symptoms with or without motor deficits. He presented asymmetrical tonic pupils, a neurogenic bladder, and mild sensory impairment in the distal parts of the bilateral lower limbs without orthostatic hypotension and motor deficits. Nerve conduction studies revealed mild axonal changes with slightly reduced conduction velocities in the lower limbs. His left pupil over-responded to instillation with 0.125% pilocarpine. Functional bladder tests showed an atonic bladder, suggesting postganglionic parasympathetic involvement. Autonomic evaluation for sympathetic components including head-up tilt, beat to beat responses to Valsalva's maneuver, cardiac MIBG imaging, plasma catecholamine levels and sweat tests were all normal. A genetic test disclosed a heterozygous mutation of myelin protein zero (MPZ); p.Thr124Met. Selectively distributed dysautonomia in this pedigree may indicate parasympathetic postganglionic components including the ganglion as the primary target of this mutated MPZ in the autonomic nervous system.

Frequency of chronic headaches in Japanese patients with multiple sclerosis: with special reference to opticospinal and common forms of multiple sclerosis.

BACKGROUND: Headache is common in Western patients with multiple sclerosis (MS), but its frequency has not been reported in Asian patients. In Asians, the opticospinal form of MS, showing similar characteristics to relapsing neuromyelitis optica in Westerners, is regarded as a different subtype from conventional MS. OBJECTIVES: The aim of this study was to clarify the frequency of primary and chronic secondary headaches in Japanese patients with MS and the factors associated with the emergence of such headaches. METHODS: We investigated 127 consecutive patients with clinically definite MS. Frequencies of primary and chronic secondary headaches were compared according to clinical subtype, administration of interferon beta, and anti-aquaporin-4 antibody status. RESULTS: The frequency of patients with primary and chronic secondary headaches at the time of interview was 64/127 (50.4%); the frequency of migraine was 26/127 (20.4%) and that of tension-type headache was 38/127 (29.9%). The frequencies of patients with primary and chronic secondary headaches and migraine without aura after the onset of MS were higher in patients undergoing interferon beta therapy than in those not on the therapy (42.4% vs 23.4%, P < .05 and 15.1% vs 4.3%, P = .05, respectively). There were no significant differences in the frequency of primary and chronic secondary headaches based on clinical subtype of MS. However, among patients not receiving interferon beta, the occurrence of migraine with aura after the onset of MS was significantly higher in patients with anti-aquaporin-4 antibody than in patients without the antibody (13.3% vs 0.0%, P < .05). CONCLUSIONS: In Japanese patients with MS, the frequency of primary and chronic secondary headaches, especially migraine, was higher than in the general Japanese population. Administration of interferon beta was related to a higher frequency of primary and chronic secondary headaches, especially migraine without aura, irrespective of clinical subtype of MS.

Transient burning pain in the ipsilateral orbit as an initial manifestation of dorsal pontine hemorrhage: case report.

A 45-year-old man with a past history of hypertension and hyperlipidemia presented with right dorsal pontine hemorrhage manifesting as transient burning pain in the right orbital region, followed by numbness and mild weakness of the left side of the body. Magnetic resonance imaging showed a hyperintense lesion in the right dorsal pons on T(1)-weighted and T(2)-weighted images, but no other abnormalities suggesting vascular lesions in the midbrain, medulla, cerebellum, or cerebrum. These findings were consistent with the subacute stage of small pontine hemorrhage. He was treated to decrease his blood pressure. The symptoms gradually improved and he has suffered neither recurrence of the orbital pain nor migraine for several months after the first episode of headache. The trigeminal nociceptive system in the dorsal lateral pons may be linked to this characteristic pain, as suggested by reports of secondary migraine caused by cavernous hemangioma and arteriovenous malformation, and activation of the dorsal lateral pons during migraine attacks on positron emission tomography.

Multimodality-evoked potential study of anti-aquaporin-4 antibody-positive and -negative multiple sclerosis patients.

Neuromyelitis optica (NMO) is claimed to be a distinct disease entity from multiple sclerosis (MS) because of its strong association with NMO-IgG/anti-AQP4 antibody; however, the in vivo role of the antibody remains unknown. Therefore, we aimed to clarify whether the presence of anti-AQP4 antibody is associated with any abnormalities in multimodality-evoked potentials in 111 patients with relapsing-remitting or relapsing-progressive MS, including the opticospinal form of MS, 18 of whom were seropositive for anti-AQP4 antibody. More patients with anti-AQP4 antibody showed a lack of the P100 component on visual-evoked potentials (VEPs) than those without the antibody (11/17, 64.7% vs. 20/84, 23.8%, p=0.003), whereas the frequency of delayed P100 latency was significantly higher in the latter group than in the former (1/17, 5.9% vs. 28/84, 33.3%, p=0.021). The frequencies of non-responses and delayed central sensory conduction times in median and posterior tibial nerve somatosensory-evoked potentials (SEPs) were not significantly different between anti-AQP4 antibody-positive and -negative patients. In terms of upper and lower limb motor-evoked potentials (MEPs), the frequencies of non-responses and delayed central motor conduction times did not differ significantly based on the presence or absence of anti-AQP4 antibody. The frequency of optic nerve lesions on MRI was significantly higher in anti-AQP4 antibody-positive patients than in anti-AQP4 antibody-negative patients (p=0.0137). Multiple logistic analyses revealed that anti-AQP4 antibody positivity (OR=8.406, p=0.02) and unevoked VEP responses (OR=35.432, p<0.001) were significantly related to development of severe visual impairment. Such an association of anti-AQP4 antibody with disability was not found for either severe motor or sensory impairment. These findings suggest a distinctive nature of optic nerve lesions between anti-AQP4 antibody-positive and -negative patients; lesions are supposed to be more necrotic in the former group and more demyelinating in the latter.

[Solitary neurofibroma presenting as a tender soft-to-firm tumor at the temporal head region masquerading as temporal arteritis].

We reported a 59-year-old woman who had complained of right temporalgia for 5 years. She was first diagnosed with a carious tooth, but treatment did not alleviate the pain. She then developed right facial pain and numbness at the right side of the tongue tip. In spite of repetitive examinations and medications, temporalgia worsened in August, 2007. Neurological examination on admission revealed a palpable soft-to-firm tumor with tenderness at the right temporal head region, right facial pain radiating to the right forehead induced by tapping on the middle of the forehead, and dysesthesia at the right tip of the tongue, C-reactive protein was negative and erythrocyte sedimentation rate was normal. Ultrasonographic examination showed beads-like tumors with low-echoic lesions without blood flow. MRI demonstrated multiple small ovoid lesions in the right subcutaneous tissue of the right temporal head. Although we initially suspected temporal arteritis, these findings were contrary. Tumor biopsy finally revealed solitary neurofibroma of the right auriculotemporal nerve. A sporadic localized intraneural neurofibroma at the extracranial region is an uncommon entity. Furthermore, nerve sheath tumors of the trigeminal nerve rarely manifest with intermittent painful burning or crawling sensations simulating trigeminal neuralgia. The present case manifested as a tumor with tenderness at the right auriculotemporal nerve and mimicked temporal arteritis. Therefore, it is important to understand that neurofibroma of the auriculotemporal nerve can mimic temporal arteritis and manifest with trigeminal neuralgia-like pain.