Brain abnormalities in Sjogren syndrome with recurrent CNS manifestations: association with neuromyelitis optica.

BACKGROUND AND OBJECTIVES: Optic neuritis or longitudinally extensive myelitis in Sjogren syndrome (SS) suggests a neuromyelitis optica spectrum disorder (NMOSD). However, brain abnormalities of SS remain to be elucidated for the association with neuromyelitis optica (NMO). METHODS: Twelve primary SS patients (all women, 42 +/- 13.2 years) who had recurrent central nervous system (CNS) manifestations with brain involvement were retrospectively identified. Brain MRI, and neurologic and serologic findings were analyzed with the measurement of anti-aquaporin-4 antibody (AQP4-Ab). RESULTS: All patients showed brain lesions characteristic of NMO as follows: 1) the involved sites adjacent to the third and fourth ventricles and in the posterior limb of the internal capsule, 2) unique configurations, such as the longitudinal course from the internal capsule to the midbrain, large cerebral or cerebellar lesions over 3 cm, and cavity-like formations. AQP4-Ab was positive in six of eight patients tested, and all the seropositive patients showed lesions with increased diffusion, suggestive of vasogenic edema. Four patients met the revised criteria of NMO, and nine had features of NMOSDs. Of the remaining three patients showing only brain involvement, one had AQP4-Ab. CONCLUSIONS: This study demonstrates that SS patients with recurrent CNS involvement have brain abnormalities characteristic of NMO and AQP4-Ab in Korea. The presence of AQP4-Ab in one SS patient with only brain involvement may suggest that the coexistence of NMO should be explored in SS patients with recurrent CNS manifestations, even without optic neuritis or myelitis.

Different clinical and magnetic resonance imaging features between Charcot-Marie-Tooth disease type 1A and 2A.

Charcot-Marie-Tooth disease type 1A (CMT1A) is the more frequent cause of demyelinating CMT, and CMT2A is the most common cause of axonal CMT. We conducted a magnetic resonance imaging (MRI) study on 39 CMT1A and 21 CMT2A patients to compare their neuroimaging patterns and correlate with clinical features. CMT1A patients showed selective fatty infiltration with a preference for anterior and lateral compartment muscles, whereas CMT2A patients showed a preference for superficial posterior compartment muscles. Early-onset CMT2A patients showed more severe leg fatty atrophy than late-onset CMT2A patients. In late-onset CMT2A, soleus muscle was the earliest, and most severely affected than the other leg muscles. Selective involvement of intrinsic foot muscles is a characteristic pattern of minimal CMT1A and CMT2A. Our MRI study demonstrates different patterns of fatty infiltration involving superficial posterior compartment muscles in CMT2A (partial T-type), and peroneal nerve innervated muscles in CMT1A (P-type).

Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations.

Mutations in the mitofusin 2 (MFN2) gene, which encodes a mitochondrial GTPase mitofusin protein, have recently been reported to cause both Charcot-Marie-Tooth 2A (CMT2A) and hereditary motor and sensory neuropathy VI (HMSN VI). It is well known that HMSN VI is an axonal CMT neuropathy with optic atrophy. However, the differences between CMT2A and HMSN VI with MFN2 mutations remained to be clarified. Therefore, we studied the phenotypic characteristics of CMT patients with MFN2 mutations. Mutations in MFN2 were screened in 62 unrelated axonal CMT neuropathy families. We calculated CMT neuropathy scores (CMTNSs) and functional disability scales (FDSs) to quantify disease severity. Twenty-one patients with the MFN2 mutations were studied by brain MRI. Ten pathogenic mutations were identified in 26 patients from 15 families (24.2%). Six of these mutations had not been reported, and de novo mutations were observed in five families (33.3%). The electrophysiological patterns of affected individuals with the MFN2 mutations were typical of axonal CMT; however, the clinical and electrophysiological characteristics were markedly different in early (<10 years) and late disease-onset (> or =10 years) groups. All patients with an early onset had severe CMTNS (> or =21) and FDS (6 or 7), whereas most patients with late onset had mild CMTNS (< or =10) and FDS (< or =3). We identified two HMSN VI families with the R364W mutation in the early onset group; however, two other families with the same mutation did not have optic atrophy. In addition, two early onset families with R94W mutations, previously reported for HMSN VI, did not have visual impairment. Interestingly, eight patients had periventricular and subcortical hyperintense lesions by brain MRI. In the late-onset group, three patients had sensorineural hearing loss and two had bilateral extensor plantar responses. We found that MFN2 mutations are the major cause of axonal CMT neuropathy, and that they are associated with variable CNS involvements. Phenotypes were significantly different in the early and late disease-onset groups. Our findings suggest that HMSN VI might be a variant of the early onset severe CMT2A phenotype.

Two missense mutations of EGR2 R359W and GJB1 V136A in a Charcot-Marie-Tooth disease family.

During mutational analysis of Charcot-Marie-Tooth (CMT) causative genes, we identified a CMT family with two missense mutations in different genes. A R359W mutation in EGR2 was shared by the affected daughter (proband) and her father. In addition, she had a V136A mutation in GJB1, which was determined to be a de novo mutation. The daughter with two different gene mutations showed more severe clinical, electrophysiological and histopathological phenotypes than her father who had only the EGR2 mutation. We suggest that these phenotypic differences between the proband and her father may have been caused by an altered effect of the genetic modifier in EGR2, or by the additive effect of the EGR2 and GJB1 mutations.

Transient improvement of pyruvate metabolism after coenzyme Q therapy in Kearns-Sayre syndrome: MRS study.

Coenzyme Q therapy has been used to support metabolic derangements in patients with mitochondrial encephalomyopathies. Biochemical analysis of the living human brain can be performed by magnetic resonance spectroscopy (MRS). We report upon a KSS patient who was serially imaged with localized proton MRS to monitor the efficacy of CoQ treatment. A 17-year-old girl with KSS was serially imaged with localized proton MRS performed on a GE 1.5 T SIGNA MRI/MRS system. The elevated lactate contents of lesions decreased after one month of CoQ therapy but were re-elevated 10 months after treatment. We conclude that MRS presents us with a powerful tool for monitoring the effects of therapeutic trials in mitochondrial encephalomyopathies.

Diffuse cerebrospinal gliomatosis with extensive leptomeningeal spread.

A case of diffuse cerebrospinal gliomatosis with extensive leptomeningeal spread is presented. The patient, an 18-year-old girl, was admitted due to progressive weakness and paresthesia of both legs, following rapid neuropsychiatric deterioration. An initial magnetic resonance imaging (MRI) study of the T-spine showed diffuse high signal intensities from T9 to T12 spinal cords on a T2 sagittal image and diffuse cord bulging at T1WI. This suggested an inflammatory lesion such as tuberculosis or fungal meningoencephalitis. A limited autopsy was performed. A microscopic examination revealed multifocal GFAP-positive astrocytic proliferations that were low grade astrocytoma in the cerebral leptomeninges, parietal, occipital and temporal lobes and anaplastic astrocytoma in the spinal cord and spinal leptomeninges. The high proliferative indices of the spinal lesion and aneuploidy correspond to a diagnosis of malignant astrocytoma and a rapid fatal clinical course.

Muscle fiber type disproportion with an autosomal dominant inheritance.

Congenital muscle fiber type disproportion (CFTD) has been described as a form of congenital myopathy characterized by the smallness and marked predominance of type 1 fibers in a muscle biopsy. Clinical manifestations include hypotonia, nonprogressive muscle weakness, joint contractures, and skeletal deformities. However, it has also been noted that the same pathologic alterations appeared in clinically diverse conditions. Recently, we experienced a family, a mother and two children, in which a muscle biopsy showed the mother to have muscle fiber type disproportion. This case was unusual in that there was a significant progression of weakness, an absence of neonatal hypotonia, and other commonly associated musculo-skeletal deformities. In this report, we describe the clinicopathologic features of the family with a brief review about muscle fiber type disproportion.

Basilar artery vasospasm in postpartum cerebral angiopathy.

The reason cerebral edema in postpartum cerebral angiopathy (PPCA) occurs preferentially in the posterior brain is poorly understood. The authors present two patients with PPCA who showed vasospasm occurring earlier and more severely in the basilar artery than in the middle cerebral artery. Our patients demonstrate the difference in vascular change between the anterior and posterior cerebral vessels, explaining the susceptibility of the posterior brain to PPCA.

Asymptomatic electrophysiologic carpal tunnel syndrome in diabetics: entrapment or polyneuropathy.

Electrophysiologic carpal tunnel syndrome (CTS) is common and is frequently asymptomatic in diabetics. In order to evaluate the clinical significance of asymptomatic electrophysiologic CTS, the nerve conduction studies (NCS) of 48 diabetics with asymptomatic electrophysiologic CTS were compared with those of 56 age and gender-matched controls, as well as 50 patients with symptomatic CTS without diabetes. Nerve conduction velocities of the ulnar, peroneal, and posterior tibial nerves were significantly slower in diabetics with asymptomatic electrophysiologic CTS than in normal controls. Compared to symptomatic non-diabetic CTS, there was also significant slowing of the median and ulnar nerve conduction velocities in asymptomatic diabetic CTS. However, in diabetics with asymptomatic CTS, abnormalities of the distal segment of the median NCS were more prominent compared with those of all the other tested nerves. These findings suggested that asymptomatic electrophysiologic CTS in diabetics is a manifestation of increased vulnerability to the entrapment of the peripheral nerve.

Sporadic inclusion body myositis correlates with increased expression and cross-linking by transglutaminases 1 and 2.

Sporadic inclusion body myositis (SIBM) is characterized by vacuolar degeneration of muscle fibers and intrafiber clusters of paired helical filaments with abnormal amyloid deposition. Because of their potential involvement in other degenerative disorders, we have examined the expression of transglutaminases (TGases) in normal and SIBM tissues. We report that at least two different enzymes, the ubiquitous TGase 2 as well as the TGase 1 enzyme, are present in muscle tissues. However, in comparison with normal tissue, the expression of TGases 1 and 2 was increased 2.5- and 4-fold in SIBM, accompanied by about a 20-fold higher total TGase activity. By immunohistochemical staining, in normal muscle, TGase 2 expression was restricted to some endomysial connective tissue elements, whereas TGase 1 and beta-amyloid proteins were not detectable. In SIBM muscle, both TGases 1 and 2 as well as amyloid proteins were brightly expressed and co-localized in the vacuolated muscle fibers, but none of these proteins colocalized with inflammatory cell markers. Next, we isolated high molecular weight insoluble proteins from SIBM muscle tissue and showed that they were cross-linked by about 6 residues/1000 residues of the isopeptide bond. Furthermore, by amino acid sequencing of solubilized tryptic peptides, they contain amyloid and skeletal muscle proteins. Together, these findings suggest that elevated expression of TGases 1 and 2 participate in the formation of insoluble amyloid deposits in SIBM tissue and in this way may contribute to progressive and debilitating muscle disease.

Brachial plexopathy caused by subclavian artery aneurysm in Behçet's disease.

As the cause of brachial plexopathy, an aneurysm of the subclavian artery is rare and mostly related to trauma. Early diagnosis and treatment is very important because the arterial aneurysm itself is life-threatening and nerve injury can be reversible in cases of early treatment. We report a patient with Behçet's disease having a right brachial plexopathy caused by a nontraumatic aneurysm of the right subclavian artery.

Clinical analysis of 12 Korean Lambert-Eaton myasthenic syndrome (LEMS) patients.

The Lambert-Eaton myasthenic syndrome (LEMS) heralds the occurrence of malignancy, especially small-cell lung cancer (SCLC), but it can also occur in the absence of cancer. Twelve patients were diagnosed as LEMS by clinical features and the classical electrophysiological triad, which includes a low amplitude of compound muscle action potentials (CMAP), decremental responses on low-rate stimulation, and incremental responses on high-rate stimulation on the repetitive nerve stimulation (RNS) test. There were 6 male and 6 female patients, ranging in age from 49 to 66 years. Malignancy(all were SCLC) was found in 7 patients. Males predominantly expressed the paraneoplastic form; whereas the primary autoimmune form was found only in women, who showed a good response to corticosteroid treatment. The neurological features were similar in both groups: proximal lower limb weakness, depressed muscle stretch reflexes, and dryness of mouth in nearly all patients. Bulbar dysfunction and limb paresthesia were a little more frequent in the paraneoplastic form. In RNS tests, the characteristic electrophysiological abnormalities were found in all patients and were more profound in the paraneoplastic form. We concluded that LEMS is commonly associated with malignancy, especially SCLC, but it should also be stressed that there are many female LEMS patients who do not harbor any malignancy at all, and that other treatment strategies such as immunotherapy should be considered for these patients.

Sympathetic skin response and cardiovascular autonomic function tests in Parkinson's disease.

Autonomic dysfunction commonly occurs in Parkinson's disease, but the pathogenesis of autonomic dysregulation remains uncertain. Autonomic functions regulating the cardiovascular system have been investigated in Parkinson's disease, but those involving the extremities has not been well demonstrated. To compare autonomic dysfunctions of the cardiovascular system with those of the extremities, we performed sympathetic skin response (SSR) and cardiovascular autonomic function tests (CAFT)-30 : 15 ratio, E : I ratio, Valsalva ratio, isometric exercise test (IET)--in 37 patients with Parkinson's disease and 33 age- and sex-matched healthy controls. The patients were asked to stop antiparkinsonian medications for at least 12 hours prior to the tests. SSR was measured at the right hand and foot after electrical stimulation of the right median and posterior tibial nerves. Absent SSR at either one or both extremities and CAFT beyond normal ranges were regarded as abnormal. Abnormal SSR was observed in 59% of patients, while abnormal CAFT were found in the range of 32%-81%. Patients with abnormal SSR showed more frequent and severe CAFT abnormalities than did patients with normal SSR. Among the CAFT, IET was well correlated with the SSR. The results suggest that parkinsonian sympathetic dysfunction involving either the cardiovascular system or the extremities may have the same pathophysiology.

Two cases of mitochondrial myopathy with predominant respiratory dysfunction.

Although it is well known that the respiratory failure is a major cause of death in most patients with chronic neuromuscular disease, predominant respiratory dysfunction without severe involvement of limb muscles is an unusual complication of mitochondrial myopathy in adult age. We experienced two cases of mitochondrial myopathy with severe involvement of respiratory function and only mild involvement of limb muscles. One is a 16 year old female and another is a 22 year old male. The diagnosis is based on morphologic characteristics of "ragged red fibers" under the light microscope and abnormal mitochondrias on the electron microscope in the muscle biopsy.

Effect of capsular infarct size on clinical presentation of stroke.

We reviewed the medical records and cranial computed tomograms of 74 patients with acute capsular infarcts to investigate the correlation between infarct size and clinical symptoms. Average infarct size varied significantly by clinical syndrome; patients with sensorimotor stroke had the largest infarcts, patients with pure motor hemiparesis had middle-sized infarcts, and patients with ataxic hemiparesis or the dysarthria-clumsy hand syndrome had the smallest infarcts. Although it has been proposed that the type of lacunar syndrome is determined entirely by the infarct location, our results suggest that infarct size is another important factor influencing the clinical presentation of lacunar syndromes.

Height, an important factor in the latency of somatosensory evoked potentials.

In a study of the relationship between height and the somatosensory evoked potentials (SEPs) in 24 normal individuals, we found significant linear correlations between height and the latencies of major peaks along the pathway in the median, ulnar, and first, third, and fifth digital SEPs. Thus, we conclude that the measured latency should be compared with the expected latency according to the subject's height before it is interpreted as normal or abnormal.

Comparison between electrophysiologic and morphologic changes in lead induced peripheral neuropathy in rats.

Compound nerve action potential (CNAP) of the mixed peripheral nerve is composed of A alpha beta, A delta, and C potentials. All components of CNAPs in the sciatic nerve were recorded by stimulating the tibial nerve of both control and lead-poisoned rats. Marked decrease of nerve conduction velocity and prolonged duration were found in A alpha beta and A delta fibers especially in large myelinated A alpha beta fibers. The amplitude decreased in A alpha beta potential, but the area did not change. In C potential produced by activation of unmyelinated fibers, nerve conduction velocity slightly decreased, but the amplitude and area did not significantly change. Pathologic correlates revealed prominent segmental demyelination with significant decrease of large myelinated fiber densities. Minimal axonal degeneration of unmyelinated fibers was present. We can conclude that electrophysiologic changes in the lead-poisoned rats correlate with pathologic changes in them.