[Over 5 years follow-up of three cases of autoimmune autonomic ganglionopathy].

We report the clinical course of three cases of anti-ganglionic acetylcholine receptor (gAChR) antibody positive auto-immune autonomic ganglionopathy (AAG) that have been followed for over 5 years. In all three cases, the symptoms improved by acute treatment, but ultimately relapsed. The first case was a female in her 20s who had a chronic history of photophobia, constipation and amenorrhea. The symptoms almost disappeared by plasma exchange, and menstruation resumed. During the course, it relapsed once after a cold. There was no recurrence of AAG during the two pregnancies. The second case was a male in his 60s who visited a hospital for the acute onset of orthostatic hypotension (OH) and psychological symptoms (infantilization and psychogenic pseudosyncope). Although IVIg was effective, it recurred frequently and was difficult to treat. However, all the symptoms disappeared eight years after the onset without any particular reasons. The third case was a female in her 80s who had a chronic history of OH. Acute treatment was effective, but AAG recurred repeatedly. Additionally, it was difficult to judge relapse because of the residual sequelae. During the course, cerebral hemorrhage due to supine hypertension or short-time blood pressure variability and femoral neck fracture caused by OH occurred. She eventually became a wheelchair. This report is clinically important because there are few reports of long-term follow-up of AAG.

Clinical features of autoimmune autonomic ganglionopathy and the detection of subunit-specific autoantibodies to the ganglionic acetylcholine receptor in Japanese patients.

Autoimmune autonomic ganglionopathy (AAG) is a rare acquired channelopathy that is characterized by pandysautonomia, in which autoantibodies to ganglionic nicotinic acetylcholine receptors (gAChR) may play a central role. Radioimmunoprecipitation (RIP) assays have been used for the sensitive detection of autoantibodies to gAChR in the serum of patients with AAG. Here, we developed luciferase immunoprecipitation systems (LIPS) to diagnose AAG based on IgGs to both the α3 and ß4 gAChR subunits in patient serum. We reviewed the serological and clinical data of 50 Japanese patients who were diagnosed with AAG. With the LIPS testing, we detected anti-α3 and -ß4 gAChR antibodies in 48% (24/50) of the patients. A gradual mode of onset was more common in the seropositive group than in the seronegative group. Patients with AAG frequently have orthostatic hypotension and upper and lower gastrointestinal tract symptoms, with or without anti-gAChR. The occurrence of autonomic symptoms was not significantly different between the seropositive and seronegative group, with the exception of achalasia in three patients from the seropositive group. In addition, we found a significant overrepresentation of autoimmune diseases in the seropositive group and endocrinological abnormalities as an occasional complication of AAG. Our results demonstrated that the LIPS assay was a useful novel tool for detecting autoantibodies against gAChR in patients with AAG.

[The peripheral mechanism of physiological pain].

Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or it is described in terms of such damage. Additionally, activity induced in the nociceptor and nociceptive pathways by a noxious stimulus is not considered pain, which is always a psychological state (IASP). Aδ- and C-fibers play important roles in conducting pain to the central nervous system. The former conducts fast pain and the latter slow pain. Intraneural microstimulation by microneurography causes mainly dull pain in glabrous skin and burning pain in hairy skin. Most of the burning pain is conducted by C-fibers, which are receptive to heating (CH) and are mechano- and heat-insensitive (CMiHi). The characters of C-fibers are easily influenced by chemical stimulants. For example, capsaicin induces sensitization to CMiHi and desensitization in the C-fibers that are mechano- and heat-responsive (CMH). Secondary hyperalgesia and allodynia have been shown to be the changes in the central network of pain, but maintenance of pain seems to require the excitation of nociceptors. Sensitization to heat is observed much more prominently in Aδ-fibers than in C-fibers. Such function of Aδ-fibers is closely related to the maintenance of pain and spontaneous pain in the case of burn injury. Physiological pain has significant importance as a warning sign that ensures human safety.

[A 34-year-old woman with cat scratch disease who developed encephalopathy].

We experienced a patient with cat-scratch disease (CSD) who developed encephalopathy. The subject was a 34-year-old female who had been aware of a low-grade fever and swollen inguinal lymph nodes for 1 month. The subject's consciousness became impaired after a headache developed, accompanied by fever, nausea, and vomiting, and she subsequently sought medical consultation. No major abnormalities were observed in the cerebrospinal fluid and cranial magnetic resonance imaging (MRI) was normal. However, necrotizing lymphadenitis was observed on contrast enhanced computed tomography (CT) of the pelvis and granulomatous changes were observed in a surgical lymph node biopsy. As the subject lived with a pet cat, PCR testing for Bartonella henselae (the CSD pathogen) was performed using a tissue biopsy. This was positive and the subject was diagnosed with CSD encephalopathy. There are very few domestic reports of CSD encephalopathy and care must be taken not to overlook this disease.

Clinical symptoms of bilateral anterior cerebral artery territory infarction.

Bilateral anterior cerebral artery (ACA) territory infarction is rare and its associated symptoms are still not well understood. We evaluated the clinical symptoms of four patients with bilateral ACA infarction. The common clinical features were various primitive reflexes and parkinsonian symptoms including akinesia, rigidity and hypophonia. Frontal release signs were present in all patients with ACA infarction even without direct involvement of the prefrontal cortex. Enhanced glabellar tap response, previously not reported in patients with ACA infarction, was the most consistent finding, and electrophysiological studies confirmed hyperexcitability of the late component of the blink reflex. The bilateral lesions in the deep white matter may be associated with the observed symptoms, reflecting functional disconnection of the medial prefrontal-subcortical circuitry.

[Additional further applications of microneurography in the future].

Microneurography has been mainly used in the field of basic science for obtaining information on the physiological phenomena of normal volunteers. Some clinical studies have been reported in the field of the autonomic nervous system. In the future, further applications of microneurography in the clinical situations will be desired. One of such situations is emergency or acute phase of cerebrovascular diseases, for example, at bedside or in intensive care units. Further, the recording equipment would be desired. A portable device was newly developed and is now available for this purpose of information acquistion. Another application of microneurography, i. e. as a research technique in a field intermediate between medical and engineering was introduced. The project aimed to develop an artificial hand that could sense various external stimuli and permit voluntary finger movement. Microneurography was used for conducting the impulses from the surface pressure transducer on the artificial hand and triggering pressure sense in the subject via microstimulation of inserted nerve fibers. Great attention should be paid to insert the needle into various tissues other than a nerve. The epoxy resin coating for insulation was stripped irregularly with the aid of observation using scanning electron microscope. The optimum stripping method for recording nerve activity when tungsten microelectrode needles are employed is still unknown. The insertion technique can be analyzed by ultrasonography. The identification of the needle on the ultrasonographic image is often difficult; however, the needle direction can be easily judged by observation of the motion of the surrounding tissue.

[Case of primary intraocular central nervous system lymphoma with high interleukin 10 level and positive cytology in cerebrospinal fluid].

A 73-year-old woman was admitted to the surgical department of our hospital for endoscopic resection of a colonic polyp. The day after endoscopic resection, she became drowsy and dysphasic. Two days later, left hemiparesis and gait difficulty developed. The next day, hemiparesis progressed bilaterally and dyspnea developed due to upper airway stenosis. The most prominent signs were those of bulbar palsy. Blood analysis revealed mild inflammatory responses and hyponatremia. T2-weighted magnetic resonance imaging showed high-intensity lesions in the swollen medulla and cervical spinal cord. Those areas and the meninges of the posterior fossa were enhanced by gadolinium. Steroid pulse therapy was administered, resulting in rapid recovery of bulbar and paretic symptoms with decreased enhanced area. At this point, concentration of cerebrospinal fluid interleukin (IL)-10 was markedly elevated at 146 pg/ml (normal,< 5 pg/ml), suggesting malignant lymphoma. Cytology of the cerebrospinal fluid was repeatedly examined, eventually revealing atypical lymphocytes with hyperlobulated nuclei and clear nucleoli. Lymphocytes stained with anti-CD20 antibody. These findings strongly suggested a diagnosis of primary intraocular and central nervous system lymphoma. In the present case, repeated cytology of cerebrospinal fluid was highly important for diagnosis in this case of high IL-10 level in cerebrospinal fluid.

[The correlation between dysphagia and involvement of the ambiguous nucleus on MRI in acute-phase lateral medullary syndrome].

In this study, the clinical features and MRI findings of 21 patients admitted for acute lateral medullary syndrome, including 10 patients with dysphagia, were examined. According to Cytoarchitecture of the Human Brain Stem (Olszewski, J & Baxter, D), MRI-identified lesions were classified into four groups based on their location (upper, middle-upper, middle-lower, and lower parts of the medulla oblongata). We also examined whether each lesion involved the ambiguous nucleus (AN). We then studied the correlation between dysphagia and involvement of the AN. Ten patients had dysphagia, which improved very quickly in all but one. In the horizontal plane, lesions of all patients with dysphagia exhibited AN involvement, suggesting that dysphagia is strongly correlated with AN involvement. Among the 8 patients with lesions in the upper part of the medulla oblongata, the lesions of 7 patients included the AN, and 6 of those 7 patients had dysphagia. Among the 5 patients with lesions in the middle-upper part of the medulla oblongata, the lesions of two contained the AN, and one of those two patients had dysphagia. Among the 6 patients with lesions in the middle-lower part of the medulla oblongata, all lesions contained the AN, but only 3 of the patients exhibited dysphagia. In both patients who had lesions in the lower part of the medulla oblongata, the lesions did not include the AN and neither patient had dysphagia. Patients who had lesions involving the AN in the rostral part of the medulla oblongata were more likely to have dysphagia than the other patients. On the other hand, half of the patients with lesions involving the AN in the middle-lower part of the medulla oblongata did not have dysphagia. This might suggest that the caudal part of the AN has little involvement in the mechanisms of dysphagia.

[Autonomic function tests for analysis of pathophysiology and prognosis of autonomic neuropathy].

It is recommended to assess each autonomic system with system-specific function tests. Pupillary and cardiocirculatory systems have a benefit to perform the tests quantitatively, but most of the other systems are measured qualitatively. The aim of the tests exist in detecting the focus and the severity of a disease. Some tests are favored to be used repeatedly for judging the recovery. Head-up tilt and Valsalva tests are not adequate to observe the short-term improvement, but serum noradrenalin level has a good correlation to the rapid recovery. Autonomic symptoms may occur due to the dysfunction not by the efferent sympathetic pathway but by the afferent in rare cases. Sympathetic overactive conditions can be observed in those situations.

A case of postmalaria neurological syndrome in Japan.

Several neurological complications are associated with severe falciparum malaria. Indeed, some patients experience a neurological syndrome after complete recovery from Plasmodium falciparum infection. Particularly, postmalaria neurological syndrome (PMNS) is a self-limiting post-infective encephalopathy that occurs within 2 months after an episode of P. falciparum infection. We describe the case of a 54-year-old Japanese man who was readmitted to our hospital with incoherent speech and markedly disturbed and uncooperative behavior after a high-grade fever that occurred after an earlier adequately treated severe P. falciparum infection. Peripheral blood smears were repeatedly negative for malaria parasites, no organisms were detected in the cerebrospinal fluid, and no hallmark lesions of acute disseminated encephalomyelitis were depicted by brain magnetic resonance imaging. The neuropsychiatric symptoms were thought to be due to PMNS. The etiology of PMNS remains unclear, but it could be mediated by an immunological mechanism and could possibly be caused by mefloquine treatment. PMNS must be considered when characteristic neurological signs and symptoms such as psychotic or acute confusional episodes, general convulsions, and tremor occur after recovery from severe P. falciparum infection treated with oral mefloquine. This is the first reported case of suspected PMNS in Japan.

[A 26-year-old woman of interval form of acute carbon monoxide intoxication with cerebrospinal fluid abnormalities].

A 26-year-old woman was admitted to our hospital for the treatment of hyperbaric oxygen therapy to acute carbon monoxide intoxication. The consciousness disturbance improved and she was discharged after 23 times of the hyperbaric oxygen therapy. However, she was readmitted because of dementia and urinary incontinence after 22 days. Diffusion-weighted images showed bright high signal intensities in the periventicular white matter and corpus callosum. The condition was considered to be an interval form of carbon monoxide intoxication. She was treated by 38 times of the hyperbaric oxygen therapy with cytochrome C and fully recovered. MRI images and cerebrospinal fluid abnormality (high protein content and IgG index) became normalized somewhat later than the improvement of the symptoms. By an investigation utilizing diffusion-weighted images, we thought that not only the demyelination which mentioned formerly, but the vasogenic edema was involving in the mechanism of these high signal intensities in the periventicular white matter of the interval form. And in the range which we searched, this is the first report which mentioned the abnormal findings of cerebrospinal fluid in an interval form of carbon monoxide intoxication. So we believe this case is very important for telling us suspected the mechanism and some indications about the treatment of an interval form.

[31-year-old gravid woman of reversible posterior leukoencephalopathy syndrome associated with HELLP syndrome after labor].

We report on a 31-year-old gravid woman with reversible posterior leukoencephalopathy syndrome (RPLS) associated with HELLP syndrome. The patient was hospitalized and underwent an emergency cesarean section at the 34th week of pregnancy due to severe toxemia. After labor her blood pressure acutely increased to 180/100 mmHg and a generalized convulsion occurred. Laboratory data revealed hemolysis, elevated liver enzymes, and low platelets, consistent with HELLP syndrome. FLAIR and Apparent Diffusion Coefficient images on MRI showed hyperintense lesions bilaterally in the posterior white matter, however Diffusion-Weighted images revealed slightly hyperintense changes in the same locations. With the use of diltiazem for blood pressure control, and anticonvulsants, convulsions disappeared and consciousness level improved. Moreover the MRI abnormalities also improved after therapy. This case was diagnosed as RPLS associated with HELLP syndrome and is the first case of an investigation utilizing Diffusion-Weighted and Apparent Diffusion Coefficient images to establish this diagnosis. Based on these results, possible mechanisms of RPLS may be vasogenic edema mediated by a cerebrovascular endothelial disturbance of cerebral vessels and a rapid blood-pressure increase due to HELLP syndrome.

[A 95-year-old female with autopsy-proven cerebral necrosis due to candidiasis who developed stroke-like manifestations].

A 95-year-old woman complained of sudden onset of disturbance of consciousness and right hemiparesis on April 20, 2003 and was admitted on the next day. She was drowsy and showed moderate right motor and sensory hemiparesis. The blood laboratory tests showed slight inflammatory reaction. A low density area was found in the left basal ganglia by brain CT, which was also coincided with the high signal region in T2, FLAIR and diffusion-MR images. The MRA of the intracerebral arteries presented no remarkable abnormality. The hemiparesis and impaired consciousness improved partially in the following week. However, she did not fully recover, since aspiration pneumonia and mild generalized inflammation continued. Percutaneous gastrostomy and intravenous hyperalimentation were started to improve her nutrition. The moderate inflammatory state persisted for several weeks. Her blood pressure suddenly fell and she died on June 12. Autopsy showed a mildly brownish and necrotic lesion from the left caudate to the putamen through the internal capsule. There was no liquefaction. On the microscopic examination, the necrosis surrounded by small vessels was consisted of numerous neutrophils and macrophages with pseudohypha and blastospore of candida. Small fragments of fungus were phagocytosed by macrophages. Small abscesses and necrotic foci due to candidiasis were observed in the bladder, kidneys, lungs, myocardium and thyroid gland. In this case, cerebral candidiasis probably occurred via hematogenous dissemination from a primary focus in the urinary tract. The intracerebral arteries revealed rather mild atherosclerotic changes and there was no occlusion by thromboembolism. Intracerebral lesion was diagnosed as candidiasis and there was no cerebral infarction by thromboembolism. If the infection occurred after cerebral infarction, there should not be any inflammatory reaction in the center of necrotic area. There have been few reports of cerebral candidal infection in patients without diabetes mellitus or immunosuppressive conditions. None of them had been diagnosed before death. Caution should be exercised for the presence of systemic candidiasis in elderly patients who are bedridden and with continuous low grade inflammatory reactions.

[A 68-year-old man of dural arteriovenous fistula at the cranio-cervical junction with dysesthesia ascending from his both toes].

We reported a 68-year-old man of dural arteriovenous fistula at the cranio-cervical junction with dysesthesia ascending from his both toes. He recognized dysesthesia at his both toes 10 months previously. Thereafter dysesthesia ascended to his girdle which was stronger as far as his girdle and gait disturbance developed. Somatosensory evoked potential (SEP) revealed delayed central conduction time. Cervical MRI showed a swelling of the spinal cord and intramedullary hyperintense lesion from the C2 to C7 level on the T2-weighted image. Moreover flow void behind the mudulla oblongata on the T2-weighted MRI was outstanding. Angiogram through right ascending pharyngeal artery revealed enlarged and tortuous anterior and posterior spinal veins at the early arterial phase. We diagnosed as dural arteriovenous fistula (AVF) and conducted intraarterial embolization. After treatment, the swelling and hyperintense lesion of the cervical spinal cord improved on MRI, and flow void behind medulla oblongata was extinguished. Gait disturbance also improved. We think that the valves of veins in the spinal cord are responsible for the tendency of higher venous pressure in outer circumference, which results in the symptom dominating in the lower extremities. We recommend that dural AVF at the cranio-cervical junction should be considered as a differential diagnosis in case with the similar clinical course to our case.

Effect of contrast material (Levovist) infusion on peak systolic velocity in middle cerebral artery using transcranial color-coded duplex sonography.

It is of crucial importance to predict the presence of stenosis in cerebral artery before occurrence of a stroke. To determine stenosis in the middle cerebral artery (MCA), we examined the effect of contrast agent (Levovist) infusion on transcranial color-coded duplex sonography (TCCD). TCCD was performed in 24 patients with MCA stenosis determined by angiography and/or magnetic resonance angiography, and 42 patients without MCA stenosis were also examined as the control group. All patients participated to assess whether an intravenous infusion of contrast agent has some influence on the peak systolic velocity (PSV) measured along the MCA. Videotaping was initiated at the administration of contrast material and continued until contrast was no longer visible in the vessels. PSV values in normal and stenotic vessels were compared. We found that PSVs were significantly higher in the stenosis group than in the control group. Difference between precontrast and postcontrast infusion was significantly greater in the stenosis group than in the control group (p < 0.05). We conclude that PSV tends to be underestimate in poor visualization of vessels. To improve accuracy of PSV measurement, contrast enhancement material should be used.

[The painful multiple mononeuropathy of acute onset in the left arm which was diagnosed as leprous neuropathy].

A 31-year-old man from Myanmar with leprous neuropathy was reported. The progress of the disease was subacute but the painful symptom at the time of the onset was acute. Multiple mononeuropathy was diagnosed by the biopsy findings of the left superficial radial nerve. He was admitted to our hospital with the complaint of the weakness of his left hand and fingers which were very painful and got worse in several weeks. Motor palsy was observed in his left ulnar, median, and radial nerves, and there was the hypesthesia or anesthesia in his left hand, forearm and the medial side of his left upper arm. On nerve conduction studies, the amplitudes of CMAP and SNAP severely diminished or not detected. The pattern was compatible with multiple mononeuropathy. The biopsy of the left superficial radial nerve was performed. The pathological findings were the destruction of nerve fascicles, replacement of nerve fibers with inflammatory cells, and Mycobacterium leprae was found with the specific stain. These findings confirmed the diagnosis of the leprous neuropathy. Leprous neuropathy is one of the commonest causes of infectious neuropathy in the world, especially in Southeast Asia. These days many foreign workers from that area are staying in Japan, and the chances to see the disease are increasing. We have to recognize leprous neuropathy as a candidate for the multiple mononeuropathy of acute onset with painful dysesthesia similar to vascular neuropathy.

[Overlap syndrome of systemic lupus erythematosus and dermatomyositis presented a large demyelinating subcortical lesion mimicking brain tumor and high level of CSF antineuronal and serum anti-ribosomal P antibodies].

We reported a 50-year-old man with an overlap syndrome of dermatomyositis and SLE, whose magnetic resonance image of the brain showed a rapidly increasing large tumor-like focal lesion unequally enhanced by Gd-DTPA in the left frontal lobe. Its pathological finding by the brain biopsy was fibrinoid necrosis, inflammatory cell aggregation around blood vessels and many myelin-laden macrophages with central necrosis. Although many cases of blood vessel injury are reported in CNS lupus, in this case the brain lesion partly took reversible course and neural symptoms such as paresis were slight and the lesion well responded to steroid. Moreover we considered that the measurement of serum anti-ribosomal P and CSF antineuronal antibodies are useful to diagnose cases as CNS lupus.