Primary degeneration of oculomotor, motor, and somatosensory systems and auditory and visual pathways in spinocerebellar ataxia type 7: A clinicopathological study in a Japanese autopsy case.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by progressive cerebellar ataxia associated with retinal degeneration. The disease is rare in Japan, and this is the first full description of clinicopathological findings in a Japanese autopsy case of genetically confirmed SCA7 having 49 cytosine-adenine-guanine (CAG) trinucleotide repeats in the ataxin 7 gene. A 34-year-old Japanese man with no family history of clinically apparent neurodegenerative diseases presented with gait disturbance, gradually followed by truncal instability with progressive visual loss by the age of 42 years. He became wheelchair-dependent by 51 years old, neurologically exhibiting cerebellar ataxia, slow eye movement, slurred and scanning speech, lower limb spasticity, hyperreflexia, action-related slowly torsional dystonic movements in the trunk and limbs, diminished vibratory sensation in the lower limbs, auditory impairment, and macular degeneration. Brain magnetic resonance imaging revealed atrophy of the brainstem and cerebellum. He died of pneumonia at age 60 with a 26-year clinical duration of disease. Postmortem neuropathological examination revealed pronounced atrophy of the spinal cord, brainstem, cerebellum, external globus pallidus (GP), and subthalamic nucleus, microscopically showing neuronal cell loss and fibrillary astrogliosis with polyglutamine-immunoreactive neuronal nuclei and/or neuronal nuclear inclusions (NNIs). Degeneration was also accentuated in the oculomotor system, auditory and visual pathways, upper and lower motor neurons, and somatosensory system, including the spinal dorsal root ganglia. There was a weak negative correlation between the frequency of nuclear polyglutamine-positive neurons and the extent of neuronal cell loss. Clinicopathological features in the present case suggest that neurological symptoms, such as oculomotor, auditory, visual, and sensory impairments, are attributable to degeneration in their respective projection systems affected by SCA7 pathomechanisms and that dystonic movement is related to more significant degeneration in the external than internal GP.

Immunological abnormalities in patients with early-onset ataxia with ocular motor apraxia and hypoalbuminemia.

Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) is a neurodegenerative disorder caused by mutation in the aprataxin (APTX)-coding gene APTX, which is involved in DNA single-strand break repair (SSBR). The neurological abnormalities associated with EAOH are similar to those observed in patients with ataxia-telangiectasia. However, the immunological abnormalities in patients with EAOH have not been described. In this study, we report that EAOH patients have immunological abnormalities, including lymphopenia; decreased levels of CD4+ T-cells, CD8+ T-cells, and B-cells; hypogammaglobulinemia; low T-cell recombination excision circles and kappa-deleting element recombination circles; and oligoclonality of T-cell receptor ß-chain variable repertoire. These immunological abnormalities vary among the EAOH patients. Additionally, mild radiosensitivity in the lymphocytes obtained from the patients with EAOH was demonstrated. These findings suggested that the immunological abnormalities and mild radiosensitivity evident in patients with EAOH could be probably caused by the DNA repair defects.

Thyrotoxicosis Presenting as Unilateral Drop Foot.

Neuromuscular disorders associated with hyperthyroidism have several variations in their clinical phenotype, such as ophthalmopathy, periodic paralysis, and thyrotoxic myopathy. We herein report an unusual case of thyrotoxic myopathy presenting as unilateral drop foot. Histopathological examinations of the left tibialis anterior muscle showed marked variation in the fiber size, mild inflammatory cell infiltration, and necrotic and regenerated muscle fibers with predominantly type 1 fiber atrophy. Medical treatment with propylthiouracil resulted in complete improvement of the left drop foot. This case expands the phenotype of thyrotoxicosis and suggests that thyrotoxicosis be considered as a possible cause of unilateral drop foot.

[A case of vascular parkinsonism associated with hyperhomocysteinemia and methylenetetrahydrofolate reductase gene variant (C677T)].

A 56-year-old man, who presented with 6 years history of difficulty in walking, was diagnosed as having vascular parkinsonism on the basis of the clinical findings of parkinsonism, pyramidal sign and the brain MRI findings of multiple lacunar infarction. Although he did not have hypertension, he had hyperhomocysteinemia and homozygous methylenetetrahydrofolate reductase (MTHFR) gene variant (C677T) as risk factors for ischemic stroke. Recent studies have shown that hyperhomocysteinemia and MTHFR gene variant are associated with small-vessel disease, suggesting that these risk factors may underlie vascular parkinsonism, particularly in patients lacking hypertension and in those with a relatively younger age at onset of this disease.

[Sporadic case of non-progressive neurogenic muscular atrophy localized in both calf muscles].

A 60-year-old woman was admitted to our hospital because of difficulty in standing on her toes. Neurological examination showed muscle weakness in both calf muscles. Her serum creatine kinase (CK) level was slightly elevated. MRI revealed hyper-intense signals localized in both the gastrocnemius and soleus muscles. Histological examinations of biopsied muscle specimens showed a marked variation in fiber size, small angular fibers, and hypertrophic and splitting fibers, but no muscle fiber necrosis or regeneration or inflammatory cell infiltration. ATPase stained sections showed small grouped atrophy of type 1 fibers. NADH-TR stained sections showed target/targetoid fibers predominantly in type 1 fibers. Dysferlin immunoreactivity was normal. Follow-up clinical evaluation for one year showed no progression. This patient was diagnosed as having an unknown type of spinal muscular atrophy or benign calf amyotrophy. Sporadic cases characterized by elderly-onset, neurogenic muscular atrophy localized in both calf muscles, and non-progressive course are extremely rare in Japan.

Characterization of the mutant ß-subunit of ß-hexosaminidase for dimer formation responsible for the adult form of Sandhoff disease with the motor neuron disease phenotype.

The adult form of Sandhoff disease with the motor neuron disease phenotype is a rare neurodegenerative disorder caused by mutations in HEXB encoding the ß-subunit of ß-hexosaminidase, yet the properties of mutant ß-subunits of the disease have not been fully determined. We identified a novel mutation (H235Y) in the ß-sheet of the (ß/α)8-barrel domain, in addition to the previously reported P417L mutation that causes aberrant splicing, in a Japanese patient with the motor neuron disease phenotype. Enzyme assays, gel filtration studies and immunoprecipitation studies with HEK293 cells transiently expressing mutant ß-subunits demonstrated that the H235Y mutation abolished both α-ß and ß-ß dimer formation without increasing ß-hexosaminidase activity, whereas other reported mutant ß-subunits (Y456S, P504S or R533H) associated with the motor neuron disease phenotype formed dimers. Structural analysis suggested that the H235Y mutation in the ß-sheet of the (ß/α)8-barrel domain changed the conformation of the ß-subunit by causing a clash with the E288 side chain. In summary, H235Y is the first mutation in the ß-sheet of the (ß/α)8-barrel domain of the ß-subunit that abolishes α-ß and ß-ß dimer formation; the presented patient is the second patient to exhibit the motor neuron disease phenotype with P417L and a non-functional allele of HEXB.

[Case of anti VGKC-complex antibody associated disorder presenting with severe pain and fasciculations predominant in unilateral upper extremity].

A 21-year-old man complained of severe pain and muscle twitching localized in his right arm. Neurological examination showed muscle fasciculations in his right forearm but no myokymia or myotonia. Needle electromyography revealed fibrillation potentials in his biceps brachii muscle and extensor carpi radialis muscle at rest but no myokymic discharges. His serum anti-voltage-gated potassium channel (VGKC)-complex antibody level was significantly high (194.2pM; controls <100pM). Although anticonvulsant therapy relieved his pain, he was readmitted to our hospital because of severe pain in his left arm and both thighs three months later. A high-dose intravenous immunoglobulin (IVIG) therapy followed by steroid pulse therapy relieved his pain. This case with neither muscle cramp nor myokymia expands the phenotype of anti VGKC-complex antibody associated disorder.

[A case of fasciitis localized in the calf muscles associated with Edwardsiella tarda sepsis].

A 49-year-old man presented with fever and pain, redness, swelling, and difficulty in walking. The serum C-reactive protein (CRP), creatin kinase (CK), and endotoxin levels were elevated. A blood culture revealed Edwardsiella tarda(E. tarda). Computed tomography (CT) showed subfascial and subcutaneous low-density areas in the lower legs, suggesting focal abscesses and edema. The patient was likely to have necrotizing fasciitis or cellulitis. He was successfully treated with several antibiotics and discharged after 43 days. Because E. tarda causes sepsis and fulminating necrotizing fasciitis with a high mortality rate in patients with an underlying illness, it should be considered a potentially important pathogen. The lack of an underlying illness may be a factor for a good outcome in this case.

Adenocarcinoma arising in a colonic interposition following a total gastrectomy: report of a case.

A segment of the transverse colon can be used for gastric reconstruction after a total gastrectomy. This report presents the case of a 68-year-old woman with primary adenocarcinoma of the colon in a segment used for reconstruction after a total gastrectomy. The interposed colon developed colon carcinoma 9 years after the gastric reconstruction. The possibility of a primary carcinoma arising in a gastric colon interposition must be considered when employing the transverse colon as a gastric substitute.

Distal anterior compartment myopathy with early ankle contractures.

Dysferlinopathies exhibit marked heterogeneity in the initial distribution of muscle involvement at the onset of the disease. We describe a Japanese patient with dysferlinopathy who exhibited distal anterior compartment myopathy (DACM) with early contractures of the ankle, whose pedigree included patients with two other types of dysferlinopathy. The existence of three phenotypes of dysferlinopathy in one pedigree is reported, indicating the involvement of molecules other than dysferlin in the pathogenesis.

[A patient with GM2 gangliosidosis presenting with motor neuron disease symptom in his forties].

Here, we report a Japanese man with adult Sandhoff disease who presented with a motor neuron disease phenotype with slow progression. At the age of 42, he noticed weakness in his legs. At the age of 46, he was admitted to our hospital. Neurological examination revealed muscle weakness and atrophy of the upper and lower extremities, and hyperreflexia of the upper extremities. Magnetic resonance imaging showed very mild cerebellar atrophy. We diagnosed him as having atypical amyotrophic lateral sclerosis. Because of the atypical course of motor neuron disease, hexosaminidase activity in peripheral leukocytes was indicated. Asseys of hexosaminidase A and hexosaminidase B showed low activities, and we found a membranous cytoplasmic body in the submucosal nerve, leading to the diagnosis of Sandhoff disease. This is the second case of a Japanese adult with Sandhoff disease presenting with a motor neuron disease phenotype, and to our knowledge, this is the latest age of onset in Japan.

[A patient with sarcoidosis needed differential diagnosis from motor neuron disease].

A 50-year-old woman lost about 10 kg of body weight within two months. Thereafter, she developed dysphagia and dysphonia. She visited our hospital and presented with a weak elevation of the soft palate, fasciculation of the tongue, hoarseness of voice, muscle weakness of the neck and extremities, and a decrement in vital capacity. She was admitted with a provisional diagnosis of motor neuron disease. The results of laboratory examinations showed an elevation in serum lysozyme and liquor protein levels, and pleocytosis in the liquor. Needle electromyography showed neurogenic changes, and bilateral hilar lymphadenopathy was revealed by computerized tomography. A biopsy specimen was excised from lymph nodes near the right anterior scalene muscle, which showed noncaseating granulomas consistent with sarcoidosis. All her symptoms improved after steroid administration. Such patients can be treatable with steroids. Moreover, the differential diagnosis from motor neuron disease is important.

[A case of cystic cavernous angioma accompanied by a fluid-fluid level on magnetic resonance imaging].

We describe the case of a patient with cavernous angioma (CA). A 44-year-old woman complained of numbness on the left side of the body as an initial symptom of the disease. The initial magnetic resonance (MR) imaging revealed a cystic mass with a fluid-fluid level without perifocal edema in the right thalamus on the T 2-weighted image (T 2WI) and T2*-weighted image (T2*WI). Her symptoms were self-controllable; therefore we decided to observe her natural course only with serial MR imaging. The cystic mass was not enhanced by gadolinium on T1-weighted images, although, we suspected the tumor was complicated by vascular malformation. Therefore, we performed cranial angiography to eliminate the possibility of bleeding from the vascular malformation. Angiography did not demonstrate tumor staining nor vascular malformation. Longitudinally, the tumor demonstrated mosaic signal intensities on each sequence with perifocal edema. Moreover, the tumor exhibited hypointensities on T2* WIs without perifocal edema. The natural history of the tumor on MR imaging exhibited a typical case of CA. Some previous reports described cystic CA with perifocal edema and vascular malformation. In our present case, we clinically diagnosed CA on the basis of the final MR imaging together with previous reports. An intra-axial fluid-fluid level is a very rare finding of MR imaging. Here, we report the case of a patient with cystic CA accompanied by a fluid-fluid level. This finding is not a pathognomonic sign of CA; although, we consider that it is very important to follow up carefully the natural history of such cases.

[Eczematous reactions after intravenous immunoglobulin therapy in two patients with Guillain-Barré syndrome and a patient with Miller Fisher syndrome].

The use of intravenous immunoglobulin (IVIG) has become an accepted treatment for patients with Guillain-Barré syndrome. Few patients develop adverse reactions to IVIG such as flushing, urticaria, eczema, chest tightness, wheezing, diaphoresis and hypotension. We report three patients who each received a five day course of IVIG at the standard dose of 0.4 g/kg/day. Two patients had Guillain-Barré syndrome, and the other had Miller Fisher syndrome. All developed eczematous reactions after 4 days from the start day of therapy to 5 days from the last day of therapy. One patient with GBS had widespread eczematous eruption with severe pompholyx lesions on the palms, fingers and soles, and spread over a period of 2 to 3 weeks to become generalized. That persisted for 4 weeks but gradually settled with desquamation by the use of topical steroids. None of our patients subsequently developed long-term or chronic eczema after the resolution of the initial cutaneous reaction. Eczematous reactions of our patients were similar to those reported in the literature and clinically typical as pompholyx. Although pompholyx has been recognized as a clinical entity, its cause remains obscure. Cutaneous reactions after IVIG infusion are recognized to be rare, but actually they may occur more frequently than our recognition, and its knowledge is essential to make the right clinical decision.

[Two cases of generalized tetanus presenting with dysphagia as an initial symptom].

We describe two patients with generalized tetanus, a 60-year-old man and a 76-year-old woman, presenting with dysphagia as an initial symptom of the disease. Eighty percent of patients with generalized tetanus manifest dysphagia on admission to a hospital. However, dysphagia is rare as an initial symptom. Both our patients had dysphagia as their initial symptom, followed by neck stiffness and trismus. We made a diagnosis of generalized tetanus based on these neurological findings in the absence of an apparent episode of trauma. After the administration of tetanus immunoglobulin on admission, they recovered without exhibiting generalized convulsion, autonomic storm, or any other serious complications. The vaccination of tetanus toxoid cannot maintain sufficient antibody titers more than ten years. Therefore, elderly people are considered susceptible to tetanus. We suggest that tetanus should be considered in the differential diagnosis of dysphagia particularly in elderly patients. We also suggest that treatment of tetanus should be initiated immediately, because tetanus still has a high mortality rate at present.

Hypocretin-1 (orexin-A) concentrations in cerebrospinal fluid are low in patients with Guillain-Barré syndrome.

It is reported that cerebrospinal fluid (CSF) hypocretin-1 (orexin-A) concentrations in patients with narcolepsy are significantly low. Human narcolepsy is also known to be closely associated with a specific human histocompatibility leukocyte antigen (HLA), suggesting that autoimmunity is involved in the pathophysiology of the disease. Thus, it is important to know whether hypocretin changes are found in definite neuroimmunological diseases such as multiple sclerosis and Guillain-Barré syndrome (GBS). The results of the present study indicate that some patients with GBS have lower levels of CSF hypocretin-1.