[Triptans and calcitonin gene-related peptide (CGRP) receptor antagonists].

While triptans, the 5-HT1B/1D agonists, are effective and generally well-tolerated in many patients up to one-third of migraine patients either may not respond well to triptans, may not tolerate their side effects, or may have contraindications that preclude their use. Recurrence, triptan-related side effects, and cardiovascular constriction effects are demerits for acute migraine treatment. CGRP receptor antagonists, the so-called gepants, were clearely designed and expected to be better than triptans. CGRP is located in sensory nerve endings around cranial blood vessels. CGRP is a strong dilator of cerebral arteries and intravenous infusion of CGRP cause a migraine attack. Olcegepant is the first selective CGRP receptor antagonist of proven efficacy in migraine. Olcegepant could only be administered intravenously and never taken beyond Phase II. Telcagepant is orally available and several completed Phase III trials have revealed positive results. In several comparative studies of telcagepant and triptans, telcegepant did not appeared more effective than zolmitriptan or rizatriptan, although it had fewer triptan-related adverse events and drug-related adverse enents. A small number of patients taking olcegepant showed marked elevation in liver transaminase levels. It was decided to discontinue development of olcegepant. New CGRP receptor antagonists would be expected for acute migraine treatment.

p.Arg332Cys mutation of NOTCH3 gene in two unrelated Japanese families with CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is a cerebrovasuclar disease caused by NOTCH3 mutations, usually localized to exons 3 and 4. This report describes the clinical and neuroradiological findings of 2 subjects of two unrelated Japanese families who shared a common p.Arg332Cys mutation. The subject from family A presented syncope attacks as the sole clinical presentation at the beginning of his disease course. The subject from family B showed recurrent ischemic attacks, followed by a large intracranial hemorrhage. This is the first report to describe the detailed phenotypes of patients with a rare p.Arg332Cys mutation in Japan.

[Novel nutritional management regimen for very long-chain acyl-CoA dehydrogenase deficiency].

We report a novel regimen of nutritional management in 22-year-old woman with myopathic form of very-long-chain acyl-CoA dehydrogenase deficiency. This regimen is based on avoidance of fasting by frequent intake of carbohydrates and substitution of medium chain triglyceride for long- and very long-chain fatty acids. Oral intake of medium amount of long-chain fatty acid (300 kcal daily) was allowed, to facilitate compliance and to escape pigmentary retinopathy. After this nutritional management and lifestyle guidance about prevention of fatigue and starvation, the patient was free from severe rhabdomyolysis for more than three years, which had forced her to hospital management nine times in seven years.

Short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA).

Short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) is a rare primary headache syndrome. The diagnostic criteria include attacks of unilateral orbital, supraorbital or temporal stabbing pain accompanied by one of the following: conjunctival injection and/or tearing, nasal congestion and/or rhinorrhea, and eyelid edema. The duration of pain is 2 seconds to 10 minutes, and the frequency of attacks is described as once a day or more. The etiology and pathology of SUNA has yet to be documented. We report an 18-year-old man with SUNA. Lomerizine hydrochloride which is used as a preventive medicine for migraine, improved his headaches.

[Calcium antagonists in the prophylactic treatment of migraine].

Calcium channel antagonists have been employed in the prophylactic treatment of migraine. Their major action is the inhibition of Ca2+ influx into smooth muscle cells that is mediated through high voltage-sensitive Ca2+ channels. These drugs had been introduced for the treatment of migraine mainly because of 2 of their effects were considered to be of potential benefit to these patients: their vasodilatory effect and their protective action against the harmful effects of hypoxia on cerebral issue. However, recent studies have provided evidence that in the central nervous system, they directly affect neuronal functions known to be calcium-dependent, such as neurotransmitter synthesis and release, inhibition of cortical spreading depression, and neuronal excitability. Although the exact mechanism of prophylactic effects calcium channel antagonists against migraine attacks remains unknown, alterations in Ca2+ channel function in the central nervous system are believed to play a key role in prophylaxis of migraine.

[Hyperalgesia with loss of temperature sensation in one side of the body due to pinpoint infarction of contralateral spinothalamic tract].

We report a 67-year-old man who presented sudden loss of temperature sensation associated with hyperalgesia in the left trunk and extremities. No abnormal lesions were found on routine magnetic resonance image (MRI) in the brain and spinal cord. He did not show common manifestations of the lateral medullary syndrome including vertigo, nystagmus, ataxia, Horner's syndrome and ipsilateral facial sensory loss. We however suspected this syndrome, because he complained of characteristic, severe pain and electrical sensations in one side of his body. Reexamined, thinly sliced T2-weighted MRI showed a very small high intensity spot in the right medulla, corresponding to the location of lateral spinothalamic tract. Oral carbamazepine was partially effective to ameliorate the intractable central poststroke pain.

Neuromyelitis optica with HTLV-1 infection: different from acute progressive HAM?

Acute variant of human T lymphotropic virus type 1 (HTLV-1)-associated myelopathy (HAM) has been postulated as termed "acute HAM" or "rapidly progressive HAM". However, it remains controversial whether HAM itself could cause such rapid progression. We report a patient with HTLV-1 infection, in whom the diagnosis of neuromyelitis optica (NMO) could be made based on relapsing-remitting course of opticospinal disturbance and positive anti-aquaporin-4 (AQP4) antibody. Careful testing of anti-AQP4 antibody is necessary to establish whether or not acute HAM is a clinical variant of HAM.

[Central nervous system leukemia mimicking rapidly progressive HTLV-1 associated myelopathy].

A 79-year-old woman was suffered from rapidly progressive paresthesia of lower limbs and gait disturbance. After one month, she showed flaccid paraplegia and hyperreflexia in the lower limbs with positive Babinski signs. Anti-HTLV-1 antibody titer was elevated in the serum, but negative in the cerebrospinal fluid (CSF). CSF examination showed mild pleocytosis, elevated protein, and normal glucose content. Adult T cell lymphoma (ATL)-like cells were seen in the CSF. MRI showed no abnormal intensity in the spinal cord and brain. Two months later, she showed rapid worsening of the paraplegia and she became unable to stand. A tentative diagnosis of rapidly progressive HTLV-1 associated myelopathy (HAM) was given, but intravenous methylprednisolone was ineffective. Six months later, she developed pneumonia, and abundant ATL cells were seen in the peripheral blood, suggesting a diagnosis of ATL. Direct infiltration of ATL cells to central nervous system was therefore suggested to have caused neurological abnormalities in this case. One may consider central nervous system leukemia when rapidly progressive HAM-like symptoms and signs are recognized, especially without positive anti-HTLV-1 antibody in the CSF.

[Case of painful muscle spasm induced by thoracic vertebral fracture: successful treatment with lumbar sympathetic ganglia block].

We report a 70-year-old man, who developed painful involuntary muscle contraction of the left leg after the lumbar discectomy, which exacerbated after a vertebral fracture of Th12. This involuntary movement was accompanied with the abnormal position of left leg simulating triple flexion response, and was induced by active or passive movement of his left knee and foot joints. Several drugs including benzodiazepines and dantrolene were ineffective, although treatment with baclofen or carbamazepine was effective. These findings suggest that hyperexcitability of the anterior horn cells following the disturbance of spinal inhibitory interneurons was involved. Electophysiological studies suggested the disturbance of left lumber nerve roots. The spinal root blocks from L3 to S1 were performed, after which the painful involuntary muscle spasm was resolved. The lumbar sympathetic ganglia block was also effective; suggesting that abnormal afferent neuronal input to spinal cord was caused by the nerve root trauma which triggered the formation of secondary abnormal network in the spine. Lumbar sympathetic ganglia block should be recommended to a therapeutic option for the refractory painful muscle spasm of the leg.

[A 61-year-old female who suffered from herpes simplex encephalitis with expanded cerebral lesions on MRI and prolonged clinical course--the diagnostic usefulness of PCR using biopsied brain tissue specimens].

A 61-year-old female developed left hemiparesis after the onset of high fever and a consciousness disturbance. Fluid attenuated inversion recovery (FLAIR) MR imaging showed high signal intensity lesions in the right temporal lobe, cingulate gyrus, and parietal lobe. Encephalitis caused by a herpes simplex virus (HSV) infection was suspected and the administration of intravenous aciclovir was thus immediately initiated. Her consciousness disturbance rapidly became exacerbated; however, the brain lesions progressively expanded to the midbrain and left hemisphere. The addition of intravenous high-dose corticosteroids to the treatment regimen ameliorated the consciousness disturbance. Although no HSV DNA was detected by repeated PCR using cerebrospinal fluid (CSF) specimens, real time PCR using a biopsied brain tissue specimens detected HSV type 1 DNA. A pathological examination showed destruction of the grey matter and a perivascular aggregation of lymphocytes, thus suggesting a diagnosis of necrotizing viral encephalitis. Immunohistochemical analysis did not reveal the presence of the HSV antigen. Hence, in the present patient failure of PCR or a serological diagnosis using CSF specimens can be ascribed to the paucity of viral particles in the brain. We therefore concluded that real-time PCR using biopsied brain tissue specimens is a novel, sensitive method for detecting causative agents in patient with prolonged and undiagnosed encephalitis.

[A case of diffuse idiopathic skeletal hyperostosis presenting dysphagia and restrictive ventilatory impairment].

We report a 65-years-old man suffering from slowly progressive dyspnea of four years' clinical history followed by dysphagia. His range of motion was severely restricted in the four extremities and trunk, however, neither motor weakness nor sensory disturbance was noted. Radiographic examination showed diffuse osteophyte formation in front of whole vertebrae but no apparent change was observed in the sacroiliac joint. These radiographic features suggested the diagnosis of diffuse idiopathic skeletal hyperostosis (DISH) in this patient. We consider that the restrictive ventilatory impairment in the present patient was due to the decreased thoracic cage compliance caused by hyperostosis of thoracic costovertebral joints, and the prominent osteophyte formation in front of the cervical vertebrae compressing esophagus was responsible for dysphagia.

[A forty-five-years-old woman suffered from Sjögren syndrome with progressive tetraparesis].

We herein report the finding of a 45-year-old woman suffered from Sjögren syndrome with progressive tetraparesis, who later developed systemic muscle atrophy and respiratory failure with a one-year clinical history. Neurological examinations revealed progressive tetraparesis with absent deep tendon reflexes, whereas no upper motor neuron signs were observed. The motor and sensory nerve conduction velocity and sensory nerve action potential (SNAP) were both completely normal, but the prolongation of distal motor latency in the median nerve and a decrease in the compound muscle action potential (CMAP) amplitude were observed. We ascertained that a spontaneous discharge was detected in her upper and lower limbs on electromyography (EMG). Her neurological findings as well as the EMG findings closely correlated with those of motor neuron disease; however, she showed a motor paralytic bladder and also demonstrated a serum antibody reaction with 50 kDa spinal cord protein of the rat. A lumbar MR image showed an increased signal intensity of the cauda equina on a gadolinium-enhanced T1 weighted image. We consider the immune-mediated impairment of the motor nerve associated with Sjögren syndrome to be the cardinal pathogenesis of the present patient, even though treatment with oral corticosteroids did not ameliorate her symptoms.

[Delayed encephalopathy following acute fentanyl intoxicication].

We report an 84-year-old woman who suffered from acute fentanyl intoxication followed by delayed encephalopathy. She used fentanyl patch at her ached knee joint and stayed in the covered table with a heat source underneath. Serum concentration of fentanyl suddenly elevated and she developed coma due to acute fentanyl intoxication. She gradually recovered, however, she showed consciousness disturbance again at 15th day and developed neurological symptoms including mutism, pyramidal tract signs, frontal lobe signs and parkinsonism. These symptoms also steadily improved without specific treatment, and became able to talk with colleagues and walk with assistance at 90th day. We considered that delayed encephalopathy due to periodic anoxia caused by fentanyl intoxication occurred in the present patient; however, the neurological sequelae were relatively mild as compared with reported cases of carbon monoxide intoxication. Neuroprotective effect of fentanyl may have contributed to the better prognosis in the present patient.

[A sixty-year-old man suffering from multiple system atrophy with pneumatosis intestinalis].

We herein report a 60-year-old man demonstrating multiple system atrophy of the cerebellar type (MSA-C) with a five-year of clinical history, who developed severe constipation followed by watery diarrhea. An abdominal CT scan showed free air in the abdominal cavity and extensive pericolic gas accumulation in the ascending and transverse colon. He was diagnosed to have pneumatosis intestinalis (PI). The air in the abdominal cavity as well as in the wall of the colon thereafter disappeared after nine days' of conservative therapy. The presense of chronic idiopathic intestinal pseudo-obstruction due to severe dysautonomia and a longstanding bed-ridden state may have been the cause of PI in this patient. This is the first case report of PI associated with MSA; however, the association of PI may have been overlooked in this disorder because of severe constipation and diarrhea, the two cardinal symptoms of PI, which happen to also be two of the typical symptoms of MSA itself.

A patient of migraine-like headache with amnesia, pleocytosis and transient hypoperfusion of cerebral blood flow.

Pseudomigraine with pleocytosis (PMP) is an uncommon disease in Japan. The diagnostic criteria include at least one episode of transient neurological deficit accompanied or followed by migraine-like severe headache, cerebrospinal fluid (CSF) lymphocytosis, and normal neuroimaging. Both the etiology and the pathophysiology of PMP is not yet well defined. We report a 40-year-old man with a PMP-like syndrome. He came to our clinic because of severe throbbing headache and amnesia, and the examination showed CSF lymphocytosis of 23/mm3, a transient decrease of cerebral blood flow in the left thalamus. All the symptoms were completely resolved within 2 months.

A case of postprandial cluster-like headache with prolactinoma: dramatic response to cabergoline.

A 17-year-old boy without a significant past medical history presented with recurrent cluster-like headaches induced by meals for 3 years. Magnetic resonance images showed a pituitary tumor. Just after starting treatment with cabergoline, the headaches resolved completely and the patient has been absolutely free from such headache attacks for 2 years.

[Corticobasal degeneration and atypical progressive supranuclear palsy: their symptomatology, laboratory examination and differential diagnosis].

Corticobasal degeneration (CBD) and atypical progressive supranuclear palsy (PSP) were reviewed with special reference to their symptomatology, laboratory examination and differential diagnosis. In our survey of the autopsy cases of CBD in Japan, only about 60% of the pathologically confirmed CBD cases were correctly diagnosed clinically, meaning that atypical (non-classical) clinical forms are common in CBD. Concerning the autopsy cases of PSP in Japan, 75% of the PSP cases had correct clinical diagnosis. In literatures, the clinically atypical CBD includes (1) frontotemporal dementia, also with primary progressive aphasia and frontal lobe dementia as subforms, (2) PSP-like form, and (3) others. The clinically atypical PSP comprises (1) pure akinesia, (2) pure easy falling syndrome (Yuasa), (3) no postural instability, (4) no gaze palsy, (5) asymmetric parkinsonism, (6) no or severe dementia, etc.. PSP with cortical manifestations such as primary progressive aphasia and CBD-like features were also reported. The atypical CBD and PSP probably reflect the distribution of tau pathology different from that in typical forms. Except for the report that phosphorylated tau is increased in CSF in CBD, but not in PSP (Urakami et al), no reliable laboratory data have been available on clinical differentiation between atypical CBD and PSP.

[Provisional diagnostic criteria of corticobasal degeneration (CBD) and the survey of patients with CBD in Japan].

We conducted the survey of patients with CBD in 2001 for 29 neurological institutions in Japan which joined Research Group on Neurodenerative Diseases supported by Ministry of Health and Welfare. Provisional diagnostic criteria of CBD were as follows: "probable CBD" means a clinical category including (1) classical form, consisting of progressive limb-kinetic apraxia and akinetic rigidity, predominant on one side, associated with late dementia, (2) quasi-classical form, revealing other corticobasal signs, predominant on one side, associated with late dementia, and (3) non-classical from, showing early aphasia, dementia, behavior disorder, etc., followed by lateralized limb-kinetic apraxia and akinetic rigidity. "Possible CBD" was not made. "Definite CBD" is pathologically confirmed CBD. There were 151 patients with "probable CBD", comprising 121 patients with classical form, 17 with quasi-classical form and 13 with non-classical from, while patients with "definite CBD" were 13. The number of patients with progressive supranuclear palsy (PSP) was also examined. The ratio of the number of patients CBD/PSP was 1/2.6 in clinical cases and 1/2.5 in autopsy cases. Nakashima et al. performed population survey of PSP patients in Yonago city in 1999, demonstrating prevalence of PSP 4.36/100,000. Considering this rate, the prevalence of CBD is assumed as 1.7 and the presumed number of PSP and CBD patients in 1999 in Japan could be 5,500 and 2,100, respectively.