Kazuya Nokura

Reversible limbic encephalitis caused by ovarian teratoma

A 19‐year‐old woman developed memory loss followed by psychosis, coma, convulsion, and central hypoventilation requiring mechanical ventilation. MRI of the brain showed minimal changes, and SPECT imaging revealed a small region of increased uptake in the cortex. Intravenous acyclovir and high‐dose corticosteroids were administered without any effect. An extensive work‐up revealed an elevated serum alpha‐fetoprotein (AFP) concentration and the presence of an ovarian tumor. Following resection of the tumor, an immature teratoma by pathology, the patient had significant recovery of her cognitive function with some psychotic sequela. Serum anti‐neuronal antibody (anti‐Hu) was negative both by immunohistochemistry and by Western blot analysis. A rare combination of paraneoplastic limbic encephalitis and brainstem encephalitis was the suspected diagnosis. Because the tumor contained a neuronal component, we propose an immunologic cross‐reaction as the pathomechanism, but the lack of a specific antibody may suggest cell‐mediated rather than globulin‐mediated immunity.

Dialysis-related spinal canal stenosis: a clinicopathological study on amyloid deposition and its AGE modification.

Three cases operated for spinal canal stenosis induced by dialysis-related amyloidosis (DRA) were investigated clinicopathologically. Cases were all-male, and had undergone hemodialysis around 20 years. In two cases, cervical plain X-rays showed only minor spondylotic changes. However, magnetic resonance imaging (MRI), myelography, and computed tomography (CT) showed extradural thickness with compression on the cervical spinal cord and cauda equina. In one case cervical X-rays showed typical destructive spondyloarthropathy (DSA), and MRI showed compression myelopathy. Surgical treatment on both cervical and lumbar spine in two cases and on cervical spine only in one case successfully reduced the symptoms. Extradural thickened tissue and ligament flavum obtained during surgery were studied histopathologically and immunostained by using anti-CD68, anti-beta2-microglobulin (beta2m), and anti-advanced glycation end product (AGE) antibody. Congo red stain showed diffuse or nodular amyloid deposition, and immunostaining with anti-beta2m and anti-AGE antibodies also demonstrated the same distribution pattern. Thus, beta2m-positive amyloid tissue in the extradural thickness (extradural amyloid deposition) was immunohistochemically demonstrated to be modified with AGE. Inflammatory reaction with histiocytic and giant cell infiltration was also shown around the amyloid tissues. There were CD68-positive cells, and some cells were positive for AGE and beta2m. These findings suggest that beta2m accumulation and inflammatory reaction finally promote destruction of connective tissues. MRI, CT and/or myelography are necessary for diagnosing spinal canal stenosis accompanied by DRA. In conclusion, we propose a more comprehensive concept of dialysis-related spinal canal stenosis, which includes both DSA and myeloradiculopathy induced by extradural thickness.

Acute motor and sensory neuronopathy associated with small-cell lung cancer: a clinicopathological study.

A 48‐year‐old Chinese woman developed ascending motor paralysis while visiting Japan, leading to tetraplegia and respiratory failure over 2 weeks. The patient’s course was complicated by anoxic encephalopathy. Nerve conduction studies revealed a severely decreased amplitude of compound muscle action potentials and a sural nerve biopsy specimen showed findings consistent with axonal‐form Guillain–Barré syndrome. An autopsy, excluding the brain, demonstrated small‐cell lung cancer that was not detected clinically, axonal‐dominant degeneration in the nerve roots and distal peripheral nerves, and the loss of both myelin and axons in the dorsal spinal column. The spinal anterior horn cells were severely decreased and were accompanied by astrocytic reaction in all spinal segments with lymphocytic infiltration. A limited examination of the dorsal root ganglia did not show Nageotte nodules, but the infiltration of T cells was observed. Although the clinical course mimicked axonal‐form Guillain–Barré syndrome, the autopsy demonstrated both sensory and motor neuronal involvement, as well as small‐cell lung cancer. Although anti‐Hu and antiganglioside antibodies were negative in the patient’s serum, the paraneoplastic mechanism might have damaged the anterior horn and dorsal root ganglia cells, which subsequently led to secondary axonal degeneration. There has been a report on a case of paraneoplastic subacute motor neuronopathy, but the acute course described here has not been reported before.

Brainstem in Machado–Joseph disease: atrophy or small size?

Machado–Joseph disease (MJD), one of the most common types of hereditary spinocerebellar degeneration caused by abnormal expansion of the CAG repeat in the MJD1 gene, presents atrophy of the infratentorial structures neuropathologically and neuroradiologically. Although a significant positive correlation has been reported between infratentorial atrophy and the number of expanded CAG repeat units, the exact changing course of brainstem size in the individual case remains to be resolved. We investigated seven cases of genetically confirmed MJD longitudinally by magnetic resonance imaging with observation periods of 4.5–10.6 years. Measurement of the midsagittal areas of infratentorial structures disclosed progressive atrophy of the pontine base and cerebellum, which correlated significantly with age, whilst midbrain and pontine tegmentum showed atrophy with no significant progression, suggesting it was better identified as ‘small size’ and might have mostly been completed before the initial symptoms. Such differences between regions in atrophy progression must be caused by a difference in the neuropathological course.

Hypersomnia, asterixis and cataplexy in association with orexin A-reduced hypothalamic tumor

Sirs: There is an absence or low level of orexin in the cerebrospinal fluid (CSF) in a majority of patients with narcolepsy-cataplexy, a chronic sleep disorder characterized by excessive daytime sleepiness (EDS) and cataplexy [6]. Orexin deficiency has been reported in several symptomatic cases of narcolepsy or hypersomnia associated with neurodegenerative, surgical, ischemic and postinfectious insults to hypothalamus [1, 5, 7]. Here we report a patient with a hypothalamic tumor and low CSF orexin A level whose symptoms improved with non-surgical therapy. We discuss the clinical presentation of orexin-reduced hypersomnia in comparison with idiopathic narcolepsy-cataplexy. A 66-year-old woman without remarkable family history was admitted to our hospital reporting symptoms typical of EDS for 1 month including falling asleep when riding in a car and during eating.Also, her family had noted that she sustained abrupt falls without loss of consciousness.Visual hallucinations also were noted but it was not of the sleep-onset type, and there was no history suggestive of sleep paralysis.Although alert, able to follow commands, and answer questions her time orientation was disturbed and she scored 21/30 on minimental state examination (MMSE). The cranial nerves, muscle tone, motor strength, and sensory were normal.When the arms were outstretched with wrists and fingers extended, abrupt downward movements of the hands occurred bilaterally consistent with asterixis. In the ward the patient suffered from facial injury from falls at night several times and she said it had been caused by an abrupt tone reduction of legs without loss of consciousness. Routine blood chemistry analysis was normal and endocrinological studies were consistent with mild anterior hypopituitarism. CSF examination revealed a protein concentration of 57 mg/dl, mild mononuclear pleocytosis, and an orexin A concentration of 62 pg/ml measured by radioimmunoassay using methodology reported previously [6]. Magnetic resonance T2 weighted images of the brain exhibited high signal intensities in the hypothalamus, thalamus, and midbrain bilaterally, with gadolinium enhancement on T1 images (Fig. 1A, B) consistent with tumor.A daytime polysomnogram demonstrated REM sleep latency of eleven minutes with five minute sleep latency. She underwent radiation therapy (total of 46 Gy), and nimustine hydrochloride and interferon β administered. The patient improved cognitively (MMSE 28/30) and behaviorally. EDS, disturbed sleep-wake cycle, falls, arm asterixis and night confusion subsided. MR images taken 4 months after completion of her therapy demonstrated reduction of tumor size and edema (Fig. 1C, D). Features of symptomatic narcolepsy or hypersommnia can vary widely according to histopathology, lesion size and location. Memory disturbance in our patient may have been due to dysfunction of amygdalofugal pathways to the ventromedial nuclei [2]. Her arms showed typical asterixis and although she had no walking difficulty in daytime she fell at night without disturbance of consciousness so we estimated that she had cataplexy-like drop attacks independent of emotional stimulus as well as upper asterixis. Similar atypical cataplexy has been reported in hypothalamic tumor cases with hypersomnia [5]. Patients with focal lesions of the basal ganglia or midbrain can show asterixis [3], but there has been no reported case having both upper asterixis and drop attack. Bril et al. have discussed the similarities between asterixis and drop attack or cataplexy and suggested upper asterixis is a segmental form of drop attack [3]. Our case also suggests that there might be common pathophysiology or anatomical site, within the hypothalamus or brainstem, for abrupt hypotonus, thus linking asterixis with cataplexy. Most cases of symptomatic narcolepsy involve lesions of the hypothalamus and rostral brainstem, and only one previously reported case fulfills the narcoleptic tetrad [7]. The reduction of orexin level supports the hypothesis that hypersomnia is caused by decreased orexin. Typically, primary narcolepsy patients show extremely low, and even undetectable levels of orexin A in the CSF [4, 6]. Narcolepsy without cataplexy or idiopathic hypersomnia cases shows only relatively low orexin levels [4]. In our patient CSF orexin A (62 pg/ml) showed relative reduction compared with controls (280 ± 33pg/ml) [6]. LETTER TO THE EDITORS

Gerstmann­Sträussler­Scheinker disease with P102L prion protein gene mutation presenting with rapidly progressive clinical course

We describe an autopsied case of a Japanese woman with Gerstmann-Straeussler-Scheinker disease (GSS) presenting with a rapidly progressive clinical course. Disease onset occurred at the age of 54 with dementia and gait disturbance. Her clinical course progressively deteriorated until she reached a bedridden state with myoclonus 9 months after onset. Two months later, she reached the akinetic mutism state. Nasal tube feeding was introduced at this point and continued for several years. Electroencephalograms showed diffuse slowing without periodic sharp-wave complexes. Diffusion-weighted magnetic resonance imaging (MRI) showed widespread cerebral cortical hyperintensity. Prion protein (PrP) gene analysis revealed a Pro to Leu point mutation at codon 102 with methionine homozygosity at codon 129. The patient died of respiratory failure after a total disease duration of 62 months. Neuropathologic examination revealed widespread spongiform change with numerous eosinophilic amyloid plaques (Kuru plaques) in the cerebral and cerebellar cortices by H & E staining. Diffuse myelin pallor with axon loss of the cerebral white matter, suggestive of panencephalopathic-type pathology was observed. Numerous PrP immunopositive plaques and diffuse synaptic-type PrP deposition were extensively observed, particularly in the cerebral and cerebellar cortices. Western blot analysis of proteinase Kresistant PrP showed a characteristic band pattern with a small molecular band of 6 kDa. The reason for the similarity in clinicopathologic findings between the present case and Creutzfeldt-Jakob disease is uncertain; however, the existence of an unknown disease-modifying factor is suspected.

Spastic tetraparesis in a patient with pseudo-pseudohypoparathyroidism

Sirs: “Pseudopseudohypoparathyroidism (PPHP)” is an entity in which patients with all the features of Albright’s hereditary osteodystrophy (AHO) have normal serum calcium and phosphate, and a normal response to parathyroid hormone (PTH). AHO is a condition in which the characteristic physical findings include a round face, short stature, brachydactyly, and ectopic calcification. AHO was first described in patients with “pseudohypoparathyroidism type Ia (PHPIa)” exhibiting resistance to PTH [1]. PPHP and PHP-Ia are genetically related variants caused by heterozygous loss-of-function mutations within the gene encoding the α-subunit of a stimulatory G protein (Gs α); this protein is necessary for the action of parathyroid and other hormones that act by stimulating the adenylate cyclase-cyclic AMP system [12]. Ossification of the posterior longitudinal ligament (OPLL), a type of paravertebral ligamentous ossification, is recognized as a cause of cervical myelopathy [9]. We describe a case of PPHP with cervical myelopathy caused by OPLL. A 53-year-old Japanese man developed difficulty in walking and limb weakness, and was admitted to our hospital for the first time in 1989. His medical history was notable for the presence of mental retardation, hypothyroidism, cerebral hemorrhage, an episode suggestive of tetany, and a diagnosis of pseudohypoparathyroidism made without further investigation. His medications at that time were L-thyroxine and vitamin D. A general physical examination revealed the typical features of AHO. When his vitamin D therapy was interrupted, serum calcium (4.6 mEq/l, normal range: 4.5–5.5), phosphate (4.0 mg/dl, normal range: 2.5–4.5), PTH (24 pg/ml, normal range: 10–65) and 1a, 25(OH)2 vitamin D (39 pg/ml, normal range: 15–70) levels were all within the normal range. The Ellsworth-Howard test revealed a normal phosphaturic response and a normal cyclic-AMP response. Therefore, the diagnosis of PPHP was confirmed. Under diagnosis and medication for hypothyroidism, antithyroid antibodies were negative; this condition may have resulted from the thyroid tissue deficiency in a Gs α-coupled transduction pathway [10]. Neurological examination revealed intact cranial nerves and mild tetraparesis without rigidity. The deep tendon reflexes were brisk. Walking was unsteady with a spastic gait. Sensation was normal. His verbal and performance IQ were 61 on the Wechsler adult-intelligence scale. CT of the head revealed bilateral and symmetrical intracranial calcifications (Figure A). A lateral radiograph of the cervical spine revealed OPLL between C2 and C5 (Figure B). CT of the cervical spine indicated severe OPLL (Figure C), and MR imaging showed severe spinal-canal stenosis and compression of the spinal cord due to OPLL and disc protrusion (Figure D, E). His symptoms gradually deteriorated over the next 10 years. Further weakness of the legs developed after he had an accidental fall in 1999. Since then, he has been confined to a wheelchair. The common neurological manifestation of PPHP and PHP-Ia is the presence of intracranial calcifications predominantly in the basal ganglia [7]. This finding has usually been reported in association with extrapyramidal symptoms [3, 13, 14]. In our patient, the lesion corresponding to the neurological symptom was cervical myelopathy associated with OPLL rather than the intracranial calcifications. Some cells from ligaments with OPLL have one of several phenotypes characteristic of osteoblasts [8]. In addition, the Gsα gene (GNAS1) has been postulated to be the leading candidate for progressive osseous heteroplasia, which is characterized by severe progressive extraskeletal bone formation within deep connective tissue and normal calcium homeostasis [4]. These features might help to explain why ossification with this particular localization developed in our patient. Although only a few PPHP or PHP-Ia cases complicated by OPLL have been reported [2, 5, 6, 11, 15], we should recognize the cervical myelopathy caused by ectopic ossification as a neurological complication in patients with PPHP.

Hypocretin-1 levels in the cerebrospinal fluid of patients with Percheron artery infarction with or without midbrain involvement: A case series.

Background:Bilateral paramedian thalamic infarctions (BPTIs) due to artery of Percheron occlusion are known to cause hypersomnia. However, the role of hypocretin-1, a wake-promoting peptide that is located at the lateral hypothalamus, in hypersomnia in these patients remains unclear. Methods:To clarify the role of hypocretin-1 in hypersomnia in patients with BPTIs, hypocretin-1 levels in the cerebrospinal fluid (CSF) were measured in 6 patients with BPTIs: 2 with rostral midbrain involvement (BPT+RMI) and 4 without midbrain involvement (BPT-MI). Results:CSF hypocretin-1 levels were decreased in 2 patients with BPT+RMI and were within normal ranges in 4 patients with BPT-MI. Hypersomnia was noted in all the patients. In one BPT+RMI patient, hypersomnia was improved within 2 weeks and decreased CSF hypocretin-1 levels were reversed (acute phase (on day 9), 109.2 pg/mL; chronic phase (at 3 months), 323 pg/mL), whereas another BPT+RMI patient who displayed coma in the acute phase had decreased CSF orexin levels (107 pg/mL) at day 49 and exhibited severe disability. Conclusion:Hypocretin deficiency was not involved in hypersomnia observed in BPT-MI patients; however, CSF hypocretin-1 levels were reduced in BPT+RMI patients. Reduced CSF hypocretin-1 levels in the chronic phase may possibly predict a poor clinical outcome in patients with Percheron artery infarction.

An autopsy case of hemiconvulsion‐hemiplegia‐epilepsy syndrome manifesting as cerebral hemiatrophy in an elderly man

We report an autopsy case of hemiconvulsion‐hemiplegia‐epilepsy (HHE) syndrome in a 79‐year‐old man. HHE syndrome usually occurs in children younger than 4 years of age. Although most HHE syndrome patients live into adult life, only a few cases of the syndrome have been reported in the elderly. In our case, cerebral hemiatrophy, left mesial temporal sclerosis and crossed cerebellar atrophy were observed. Because this is the oldest case ever reported, we further investigated age‐related neuropathological changes and found an interhemispheric difference in amyloid‐β‐related neuropathologic changes. There were almost no senile plaques or amyloid‐laden vessels in the left hemisphere. As far as we know, this is the first report of age‐related neuropathology in a brain manifesting HHE syndrome.

Posterior canal-type ocular tilt reaction caused by unilateral rostral midbrain hemorrhage

A 56-year-old man receiving treatment for hypertension experienced sudden-onset dizziness and was admitted to our hospital. Computed tomography of the brain revealed a small high-density lesion in the right rostral midbrain. Subsequent magnetic resonance imaging revealed a small hemorrhagic lesion in the same position. The patient complained of double vision affecting the right side when viewing a horizontal linear target. Vergence was intact, but vertical gaze was severely restricted downward and moderately restricted upward. Vestibulo-ocular reflex maneuvers did not alleviate the patients vertical gaze palsy. By 40 days after the incident, his motility had recovered and he could begin to tilt his head to the left. Consecutive Hess tests demonstrated a skew deviation of right hypertropia, which continued for over two years. Funduscopic examination revealed left extorsion but no right intorsion. A diagnosis of posterior canal-type ocular tilt reaction (OTR) was made from these signs. The patients course indicated that periaqueductal syndrome dominated in the acute stage whilst unilateral symptoms became more apparent in the chronic stage. The rostral interstitial nucleus of the medial longitudinal fasciculus and the posterior commissure were estimated to contain the main causative lesion for the acute symptoms, whereas the interstitial nucleus of Cajal (INC) was implicated in the chronic stage. Posterior canal-type OTR caused by unilateral INC lesion has been reported only rarely.