A case of non-dystrophic myotonia with concomitant mutations in the SCN4A and CLCN1 genes.

Non-dystrophic myotonias are caused by mutations of either the skeletal muscle chloride (CLCN1) or sodium channel (SCN4A) gene. They exhibit several distinct phenotypes, including myotonia congenita, paramyotonia congenita and sodium channel myotonia, and a genotype-phenotype correlation has been established. However, there are atypical cases that do not fit with the standard classification. We report a case of 27-year-old male who had non-dystrophic myotonia with periodic paralysis and two heterozygous mutations, E950K in CLCN1 and F1290L in SCN4A. His mother, who exhibited myotonia without paralytic attack, only harbored E950K, and no mutations were identified in his asymptomatic father. Therefore, the E950K mutation was presumed to be pathogenic, although it was reported as an extremely rare genetic variant. The proband experienced paralytic attacks that lasted for weeks and were less likely to be caused by CLCN1 mutation alone. Functional analysis of the F1290L mutant channel heterologously expressed in cultured cells revealed enhanced activation inducing membrane hyperexcitability. We therefore propose that the two mutations had additive effects on membrane excitability that resulted in more prominent myotonia in the proband. Our case stresses the value of performing genetic analysis of both CLCN1 and SCN4A genes for myotonic patients with an atypical phenotype.

[Successful corticosteroid therapies in a case of acute motor, sensory, autonomic neuropathy after cytomegalovirus infection].

We report a rare case of autonomic neuropathy associated with cytomegalovirus (CMV) infection. The patient, a 53-year-old male, was admitted to our hospital because of prolonged fever, headache and neck stiffness followed by urinary retention. Cerebrospinal fluid examination revealed pleocytosis (219/mm(3), predominantly lymphocytes) with a markedly increased protein level (217 mg/dl) and serum IgM anti-CMV antibody was detected. While his meningitic symptoms gradually improved after intravenous administration of ganciclovir, he complained of numbness in the extremities and difficulty in walking. Neurologically, marked orthostatic hypotension, glove and stocking type of paresthesia, severe muscle weakness in extremities, and neurogenic atonic bladder were noted. Nerve conduction studies showed normal except for F-waves, which were absent in the left tibial nerve. A sural nerve specimen appeared normal in both myelinated and unmyelinated fibers. He was given immunological therapies such as corticosteroid and intravenous high dose immunoglobulin therapies. After corticosteroid therapies, not only sensory and motor symptoms but also autonomic symptoms remarkably improved. Of the anti-ganglioside antibodies, IgM anti-GM1 antibody and IgM anti-GM2 antibody were detected. Although some cases with Guillain-Barré syndrome preceded by CMV infection have been reported, few cases with autonomic neuropathy have been described in association with successful corticosteroid therapies.

[A case of eosinophilic myositis presenting with myocarditis and cardiac embolism].

We report the case of a 72-year-old male who presented with the complaints of muscular pain and weakness. The patient showed marked eosinophilia, elevated levels of myogenic enzymes and pathological abnormalities including eosinophil infiltration obtained from the muscle biopsy. Based on these findings, the patient was diagnosed with eosinophilic myositis. During follow-up, left ventricular wall motion abnormalities with transient electrocardiographic abnormalities were identified; these were believed to be concurrent with eosinophilic myocarditis. Further, notable complications included cardiogenic cerebral embolism. Eosinophilic myositis has been found to cause a wide spectrum of complications. Our findings indicate that in cases of suspected eosinophilic myositis, it is crucial to identify myocarditis immediately and to select an anticoagulant therapy to prevent cerebral embolism.

Successful treatment of granulomatous amoebic encephalitis with combination antimicrobial therapy.

Granulomatous amoebic encephalitis (GAE) is a rare but fatal infection. Due to its nonspecific symptoms and laboratory and neuroradiological findings, it is rarely diagnosed antemortem. We herein present the case of a 72-year-old Japanese woman who was diagnosed with GAE following the detection of a pathogen similar to Balamuthia mandrillaris under a microscopic examination of cerebrospinal fluid sediment and who achieved remission with combination antimicrobial therapy. There are no previous reports of pathogens similar to B. mandrillaris being detected in cerebrospinal fluid antemortem; therefore, this case may be used as a benchmark for further studies.

Co-localization of hippocampal cholinergic neurostimulating peptide precursor with collapsin response mediator protein-2 at presynaptic terminals in hippocampus.

Hippocampal cholinergic neurostimulating peptide (HCNP) induces the synthesis of acetylcholine in medial septal nucleus in vitro and in vivo. HCNP precursor protein (HCNP-pp) is a multifunctional protein that participates in a number of signaling pathways, including MAPK/extracellular signal and G-protein-coupled receptor kinase 2. We recently demonstrated that the amount of collapsin response mediator protein-2 (CRMP-2) is increased in hippocampus of HCNP-pp transgenic mice. To clarify the interaction between HCNP/HCNP-pp and CRMP-2 and its role in synaptic function, we investigated whether HCNP-pp is localized to the synapse and if it affects protein expression. Here, we demonstrate that HCNP-pp co-localizes with CRMP-2 at presynaptic terminals. Furthermore, HCNP-pp overexpression increases synaptophysin levels. These findings suggest that HCNP-pp, in association with CRMP-2, plays an important role in presynaptic function in the hippocampus.

The spectrum of clinicopathological features in pure autonomic neuropathy.

We assessed the clinicopathological features of nine patients with pure autonomic neuropathy, that is, neuropathy without sensory or motor deficits. The duration from symptom onset to diagnosis ranged from 1 month to 13 years. Of eight patients in whom serum antiganglionic acetylcholine receptor antibody was determined, four were positive. All patients who tested positive for this antibody manifested widespread autonomic dysfunction, with the exception of one patient who only experienced orthostatic hypotension. However, patients who were negative for the antiganglionic acetylcholine receptor antibody presented with partial autonomic failure. One of these patients had diffuse parasympathetic failure and generalized hypohidrosis but no orthostatic hypotension, which is clinically compatible with postganglionic cholinergic dysautonomia. Electron microscopic examination revealed a variable degree of reduction in unmyelinated fibers. Compared with normal controls, the patients had a significantly increased density of collagen pockets (p < 0.05). Additionally, the percentage of Schwann cell subunits with axons (out of the total number of Schwann cell subunits associated with unmyelinated fibers) was significantly decreased (p < 0.01). The density of unmyelinated fibers tended to decrease with increasing time between the onset of autonomic symptoms and biopsy (p < 0.05). In conclusion, the clinical and pathological features of pure autonomic neuropathy vary in terms of progression, autonomic involvement, presence of the antiganglionic acetylcholine receptor antibody, and loss of unmyelinated fibers.

Longitudinal study on MRI intensity changes of Machado-Joseph disease: correlation between MRI findings and neuropathological changes.

To disclose the neuropathological progression course of Machado-Joseph disease (MJD), magnetic resonance imaging (MRI) findings of six genetically confirmed MJD cases (four males and two females, including an autopsied female, all unrelated to one another) were further investigated on neurodegeneration. Brain MRI studies were repeated in all cases at different stages of the disease. Ages at the first MRI study ranged from 47 to 65 years (55.2 ± 7.1), with observation periods from 4.5 to 10.6 years (6.95 ± 2.48). We paid particular attention to two types of previously reported MRI findings detectable using T2-weighted images. One is located just outside the internal capsules, and another in the pons. A linear high-intensity change along the internal capsules was detected in all cases, and showed progression during the observation period. A comparison between MRI and autopsy findings suggested that the lesion might reflect degeneration with neuronal loss, astrocytosis, and gliosis in the internal segment of the globus pallidus. A cross-shaped high-intensity change in the pons was well advanced but still incomplete in all cases. In this region, pontine transverse fibers were atrophic, while longitudinal fibers remained intact. Pontine nuclei showed apparent nerve cell loss, and the remaining cells had many 1C2-positive intranuclear inclusions. Since these findings were detected both by lifetime images and by postmortem examination, MRI intensity changes could track the progression of neurodegeneration. Based on a comparison between MRI findings and neuropathology, the degeneration of an internal segment of the globus pallidus (one of the pathological features of MJD) had progressed following the initial symptoms.

Decrease in myocardial 123I-MIBG radioactivity in REM sleep behavior disorder: two patients with different clinical progression.

Although decrease in myocardial iodine-123 metaiodobenzylguanidine ((123)I-MIBG) radioactivity has been reported in patients with rapid eye movement (REM) sleep behavior disorder (RBD), its pathophysiology has not been thoroughly disclosed. We report two RBD patients with differing clinical progression, in whom myocardial (123)I-MIBG scintigraphy was performed. One 69-year-old patient had more than a 20-year history of idiopathic RBD and showed a decrease in myocardial (123)I-MIBG radioactivity. The other 69-year-old patient started to manifest nocturnal behaviors at age 62, then mild parkinsonism at age 68, and showed a similar decrease in myocardial (123)I-MIBG radioactivity both before and after the onset of parkinsonism. These cases suggest that RBD could develop in diverse patterns of clinical progression even if signs of underlying Lewy body pathology are uniformly indicated.

[A case of hypertrophic cranial pachcymeningitis in a patient with lymphocytic hypophysitis].

We report a 67-year-old man of lymphocytic hypophysitis complicated by hypertrophic cranial pachcymeningitis. The hypophysitis presenting with central diabetes insipidus caused isolated adrenocorticotropic hormone (ACTH) deficiency after three years and two months since the onset of his illness. Moreover he suffered from left cavernous sinus syndrome after four years. Brain gadolinium (Gd) enhanced MRI, which was obtained in 2001, showed only enhancement of the pituitary stalk. However, brain Gd enhanced MRI, performed four years later, showed not only a remarkable thickening and enhancement of the pituitary stalk but also abnormal enhancement of the lesion in the left cavernous sinus. In addition, it showed diffuse thickening and enhancement of the dura mater. This clinical course suggested that chronic inflammation of the pituitary had spread to the dura mater, a clinical condition differing from parasellar chronic inflammatory disease (PSCID). In addition, because diffuse thickening and enhancement of the dura mater was present, it was likely that lymphocytic hypophysitis was complicated by hypertrophic cranial pachcymeningitis due to autoimmune reactions. We should carefully observe cases of lymphocytic hypophysitis and assess change over time in the dura mater of the whole brain by Gd enhanced MRI.

[A case of transient blindness due to severe stenosis of the internal carotid artery with persistent primitive hypoglossal artery (PPHA)].

We report a patient having transient blindness due to severe stenosis of the internal carotid artery (ICA) with persistent primitive hypoglossal artery (PPHA). This 73 year-old man was admitted because of the transient visual impairment. At first, he had bilateral blindness for a several minutes and after that the right amaurosis continued for an hour. MRI showed an old lacunar infarction of the right caudate nucleus. Carotid duplex ultrasonography and conventional angiography demonstrated severe stenosis of the origin of the right ICA, and PPHA was arising from the right ICA at the level of 2nd cervical spine. The left ICA was normal. Because of the aplasia of the right vertebral artery and hypoplasia of the left vertebral artery, almost all blood flow of the basilar artery was supplied from the right ICA via PPHA. We considered that transient ischemia of both the bilateral posterior cerebral arteries and the right ocular artery occurred due to stenosis of the right ICA which branching PPHA. When ischemic neurological symptoms of multiple vascular territories occurr at the same time, we often think that ischemic mechanism was cardiogenic embolism. But we should recognize that stenosis of the ICA with PPHA cause the complex neurological deficits.

CADASIL with NOTCH3 S180C presenting anticipation of onset age and hallucinations.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited disease leading to strokes and vascular dementia. The average age of onset for stroke is 45 years with a range of about 30 to 70 years. We describe a Japanese CADASIL family showing S180C in the exon 4 of NOTCH3, presenting an anticipation of the onset age for stroke. MRI demonstrated a similar extent of white matter involvement in younger and older individuals, supporting the presence of anticipation. In addition, hallucinations in 71% of affected patients, and delusions in 57% were also described. Our findings in this family suggest that a specific NOTCH3 mutation was related to unique clinical features, although such correlations have seldom been encountered in CADASIL.

[An autopsy case of purulent meningitis, presenting high signals in subarachnoid space and ventricles in diffusion weighted images (DWIs)].

A 79-year-old, bedridden woman with an untreated colon cancer, developed abrupt disturbance of consciousness and high fever. Brain MRI showed significant high signals in the subarachnoid space and ventricles in diffusion-weighted images (DWIs), and she died on the same day. At autopsy, much exudate was found over the base of the brain, leading to a diagnosis of purulent meningitis. On histological findings, inflammatory cell infiltration was significantly restricted within the subarachnoid space, but not into the brain parenchyma. This case report demonstrated that high signals in subarachnoid space and ventricles in DWIs may be very useful for diagnosis of purulent meningitis.