Pilot trial of etanercept in the treatment of inclusion-body myositis.

Inclusion-body myositis (IBM) is an inflammatory muscle disease that has proven resistant to treatment. Tumor necrosis factor molecules have been detected in muscle biopsies from patients with IBM. Etanercept is a TNFalpha receptor fusion protein that binds and inactivates tumor necrosis factor. Nine patients were treated with etanercept at a dose of 25 mg, two times a week for an average of 17 +/- 6.1 months. Each patient was evaluated using quantitative strength testing. Their data were compared to two different control groups. The first control group consisted of patients who participated in trials of beta-interferon-1A and had received placebo. There was no significant difference. The second control group was a natural history cohort of IBM patients. There was no statistically significant difference between the treated group and the natural history group at 6 and 12 months when looking at elbow flexors, or 6 months when looking at hand grip. In the treated patients there was a small but significant improvement (p = 0.002) in handgrip at 12 months.

Myopathy with skeletal asymmetry and hemidiaphragm elevation is caused by myotubularin mutations.

The authors report two families with a myopathy phenotype affecting only women, marked by asymmetric weakness, skeletal asymmetry, and an elevated hemidiaphragm. One family had a mutation in a stop codon in exon 9 of the myotubularin gene, and the other had a splice site mutation in exon 13. Both families had manifesting and nonmanifesting carriers. Skewed X-inactivation appeared to explain the clinical manifestations in only one of the two families.

Axonal multifocal motor neuropathy without conduction block or other features of demyelination.

BACKGROUND: Conduction block is considered an essential finding for the distinction between motor neuropathies and lower motor neuron disorders. Only a small number of reports describe patients with multifocal motor neuropathies who lack overt conduction block, although in these cases other features of demyelination still suggest the presence of a demyelinating disorder. In contrast, a purely axonal multifocal motor neuropathy has not been described. METHODS: This report describes nine patients with slowly or nonprogressive multifocal motor neuropathies who had purely axonal electrodiagnostic features. RESULTS: GM1 antibodies titers were normal in all nine cases. Six patients were treated with either prednisone or IV immunoglobulin and three showed convincing improvement. CONCLUSIONS: These findings suggest an immune-mediated motor neuropathy with axonal electrophysiologic features that appears to be distinct from both multifocal motor neuropathy and established motor neuron disorders.

Gene transfer mediated by recombinant baculovirus into mouse eye.

PURPOSE: To determine the efficiency of baculoviruses (BVs) to transfer recombinant genes in vivo into murine ocular tissues. METHODS: Recombinant (r)BVs carrying fluorescent protein (FP) cDNA under the control of cytomegalovirus (CMV) immediate early promoter were constructed. Initially, cultured HEK293 and ARPE19 cells were infected with these rBVs and analyzed for efficiency and stability of transgene expression. The rBV-CMV green (G)FP was also injected into the intravitreal and subretinal space of mouse eye. Mice were periodically analyzed to determine the efficiency and stability of expression by histologic examination under fluorescence microscopy. The effect of rBV-CMV-GFP on the physiology of the retina was analyzed by electroretinography. RESULTS: cDNAs encoding fluorescent proteins were efficiently transduced in HEK293 and ARPE19 cells in vitro. GFP expression in vivo was observed exclusively in retinal pigment epithelial (RPE) cells after subretinal injections. Intravitreal injections of rBV resulted in GFP expression in the corneal endothelium, lens, RPE, and retina. GFP expression was observed for up to 14 days after injection. The infiltration of macrophages, observed 2 days after injection in the area of GFP transduction, had dissipated by day 8 after injection. No alteration in ERG responses was observed 6 weeks after injection of rBV-CMV-GFP. CONCLUSIONS: BV efficiently transduces cultured RPE cells and many cell types in vivo in the eye, including endothelial, epithelial, and neuronal cells. BV may be a useful vector for transferring genes in cultured cells and in vivo into ocular tissue.

Clinical and genetic aspects of distal myopathies.

Although most muscle disorders produce proximal weakness, some myopathies may manifest predominantly or exclusively distal weakness. Although several congenital, inflammatory, or metabolic myopathies may produce mainly distal weakness, there are several distinct entities, typically referred to as distal myopathies. Most of these are inherited conditions. The distal myopathies are rare, but characteristic clinical and histological features aid in their identification. Advances in molecular genetics have led to the identification of the gene lesions responsible for several of these entities and have also expanded our understanding of the genetic relationships of distal myopathies to other inherited disorders of muscle. This review summarizes current knowledge of the clinical and molecular aspects of the distal myopathies.

Clinical spectrum of chronic acquired demyelinating polyneuropathies.

A number of presentations of chronic demyelinating polyneuropathy have been identified, each distinguished by its phenotypic pattern. In addition to classic chronic inflammatory demyelinating polyneuropathy (CIDP), which is characterized clinically by symmetric proximal and distal weakness and sensory loss, several regional variants can be recognized: multifocal motor neuropathy (MMN: asymmetric and pure motor), multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy (asymmetric, sensory, and motor), and distal acquired demyelinating symmetric (DADS) neuropathy (symmetric, distal, sensory, and motor). There are also temporal, pathological, and disease-associated variants. This review describes a clinical scheme for approaching the chronic acquired demyelinating polyneuropathies that leads to a rational use of supportive laboratory studies and treatment options. In addition, we propose new diagnostic criteria for CIDP that more accurately reflect current clinical practice.

Cervicobrachial involvement in diabetic radiculoplexopathy.

Diabetic radiculoplexopathy is commonly viewed as a condition affecting the lower extremities. However, other regions may also be affected and the presence of upper extremity involvement has rarely been emphasized. Our goal was to illustrate the clinical features of arm involvement in this condition. Of 60 patients with diabetic lumbosacral radiculoplexopathy, we identified 9 who also had upper extremity involvement. The study included 8 men and 1 woman, ranging in age from 36 to 71 years. Upper limb involvement developed simultaneously with the onset of lower limb disorder in 1 patient, preceded it by 2 months in another patient, and occurred between 3 weeks and 15 months later in the remaining 7. In 5 cases, arm involvement developed after symptoms in the legs began to improve. The upper extremity weakness affected the hands and forearms most severely. It was unilateral in 5 patients and bilateral but asymmetric in 4. Pain was often present, but it was not a prominent feature. In most patients, neurologic deficits in the arms improved spontaneously after 2-9 months. We conclude that diabetic radiculoplexopathy may involve the cervical region before, after, or simultaneously with the lumbosacral syndrome. The upper limb process is similar to that in the legs, with subacutely progressive weakness and pain followed by spontaneous recovery.

Prevalence of mutations causing retinitis pigmentosa and other inherited retinopathies.

Inherited retinopathies are a genetically and phenotypically heterogeneous group of diseases affecting approximately one in 2000 individuals worldwide. For the past 10 years, the Laboratory for Molecular Diagnosis of Inherited Eye Diseases (LMDIED) at the University of Texas-Houston Health Science Center has screened subjects ascertained in the United States and Canada for mutations in genes causing dominant and recessive autosomal retinopathies. A combination of single strand conformational analysis (SSCA) and direct sequencing of five genes (rhodopsin, peripherin/RDS, RP1, CRX, and AIPL1) identified the disease-causing mutation in approximately one-third of subjects with autosomal dominant retinitis pigmentosa (adRP) or with autosomal dominant cone-rod dystrophy (adCORD). In addition, the causative mutation was identified in 15% of subjects with Leber congenital amaurosis (LCA). Overall, we report identification of the causative mutation in 105 of 506 (21%) of unrelated subjects (probands) tested; we report five previously unreported mutations in rhodopsin, two in peripherin/RDS, and one previously unreported mutation in the cone-rod homeobox gene, CRX. Based on this large survey, the prevalence of disease-causing mutations in each of these genes within specific disease categories is estimated. These data are useful in estimating the frequency of specific mutations and in selecting individuals and families for mutation-specific studies.

Pathologic findings in late endophthalmitis after glaucoma filtering surgery.

OBJECTIVE: To report the clinicopathologic features of four eyes enucleated for late-onset bleb-related endophthalmitis. STUDY DESIGN: Retrospective case series. MATERIALS: Four enucleated eyes. METHODS: The clinical and histopathologic features of four patients who underwent enucleation for late-onset endophthalmitis after glaucoma filtering surgery were reviewed. RESULTS: The eyes were enucleated for endophthalmitis one to five years after trabeculectomy. Two of the four eyes had trabeculectomy with adjunctive mitomycin-C. All four eyes had streptococci cultured from the aqueous and/or vitreous. Common pathologic features included inflammation involving the anterior segment, lens and choroid. One eye exhibited focal granulomatous uveitis. CONCLUSIONS: Late-onset endophthalmitis after glaucoma filtering surgery is often due to streptococcal species and rapidly progresses over a few days. Phacoanaphylaxis with associated granulomatous uveitis may contribute to the poor prognosis in this setting.

Lim2(To3) transgenic mice establish a causative relationship between the mutation identified in the lim2 gene and cataractogenesis in the To3 mouse mutant.

PURPOSE: Lim2 is the gene encoding the ocular lens-specific intrinsic membrane protein MP19. We previously reported finding a single nonconservative G->T transversion in exon two of the Lim2 gene. This mutation was linked to the cataract in the To3 (Total opacity number 3) mouse mutant, confirming Lim2 as an ideal candidate gene for the To3 cataract. The aim of the present study was to substantiate a causative relationship between the mutation in the Lim2 gene and cataractogenesis in the To3 mouse mutant. To this end a Lim2To3 transgene cassette was engineered and introduced into fertilized normal mouse embryos to test its ability to induce cataractogenic lens development. METHODS: A Lim2 genomic clone was isolated and purified from a murine 129/SvJ genomic library. A restriction endonuclease map of the gene was generated using classical Southern techniques. The murine Lim2 promoter was characterized by transfecting primary chicken lens epithelial cells with Lim2 promoter-CAT reporter constructs and assaying promoter activity and specificity. This genomic clone was then used in conjunction with PCR to generate a Lim2To3 transgene cassette. After sequencing of the PCR engineered portion, the Lim2To3 transgene was then used to generate Lim2To3 transgenic mice via pronuclear injection. Founder mice and their offspring from outcrosses and intercrosses were characterized by ophthalmic examination, PCR and Southern DNA analysis, RT-PCR mRNA analysis, and histology of lens sections. RESULTS: Two mice, from independent microinjections, were identified as positive for presence of the Lim2To3 transgene cassette as well as presence of bilateral congenital cataracts and reduced eye size and mass. One of these founders was incapable of germline transmission of the transgene to offspring and was not characterized further. The other was capable of germline transmission and was characterized as described above. PCR DNA analysis revealed a perfect concordance between presence of the Lim2To3 transgene cassette and congenital cataract in offspring of this founder. Transgenic hemizygotes exhibited cataract and a reduction in eye and lens size and mass, while transgenic "homozygotes" presented with a more severe cataract and microphthalmic reduction in eye and lens size and mass. Southern analysis revealed approximately 2 copies of the transgene cassette integrated into a single chromosomal site in the founder and all hemizygous offspring. RT-PCR analysis revealed a very low ratio of Lim2To3 transgenic mRNA compared to endogenous normal Lim2. Finally, histology revealed that lens development was abnormal in mutant transgenic animals by embryonic day E15. By E19, just prior to birth, gross disorganization of secondary fibers was observed in mutants. CONCLUSIONS: These transgenic experiments firmly establish a causative relationship between the previously identified mutation in the Lim2 gene and cataractogenesis in the To3 mouse mutant. The low levels of mutant mRNA produced by the transgene cassette as compared to endogenous levels of normal Lim2 mRNA provides evidence that this dominant mutation results in a mutant MP19 protein with altered function rather than simply loss of function.

Motor neuron presentation of an ulnar neuropathy and Riche-Cannieu anastomosis.

A Riche (7)-Cannieu (2) anastomosis (ulnar-to-median anastomosis in the hand) in the setting of an ulnar or median nerve lesion can produce confusing clinical and electrodiagnostic findings. We report a patient with a deep branch ulnar neuropathy complicated by a Riche-Cannieu anastomosis. His clinical presentation led to an initial diagnosis of motor neuron disease. Extensive electrophysiologic studies clarified the extent of the Riche-Cannieu anastomosis and the ulnar neuropathy.

Distal acquired demyelinating symmetric neuropathy.

OBJECTIVE: To characterize an acquired, symmetric, demyelinating neuropathic variant with distal sensory or sensorimotor features. BACKGROUND: Classic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients have prominent proximal and distal weakness. However, chronic demyelinating neuropathies may present with different phenotypes. An approach that distinguishes these disorders primarily according to the pattern of weakness may be useful to the clinician. METHODS: A total of 53 patients with acquired symmetric demyelinating polyneuropathies were classified primarily according to the pattern of the neuropathy and secondarily according to the presence and type of monoclonal protein (M-protein) in this retrospective review. The authors distinguished between patients with distal sensory or sensorimotor involvement, designated as distal acquired demyelinating symmetric (DADS) neuropathy, from those with proximal and distal weakness, who were designated as CIDP. RESULTS: M-proteins were present in 22% of patients with CIDP. There were no features that distinguished clearly between CIDP patients with or without an M-protein, and nearly all of these patients responded to immunomodulating therapy. In contrast, nearly two-thirds of the patients with DADS neuropathy had immunoglobulin M (IgM) kappa monoclonal gammopathies, and this specific combination predicted a poor response to immunomodulating therapy. Antimyelin-associated glycoprotein (anti-MAG) antibodies were present in 67% of these patients. CONCLUSION: Distinguishing acquired demyelinating neuropathies by phenotype can often predict the presence of IgM kappa M-proteins, anti-MAG antibodies, and responses to immunomodulating therapy.

Brachial amyotrophic diplegia: a slowly progressive motor neuron disorder.

OBJECTIVE: To describe a sporadic motor neuron disorder that remains largely restricted to the upper limbs over time. BACKGROUND: Progressive amyotrophy that is isolated to the upper limbs in an adult often suggests ALS. The fact that weakness can remain largely confined to the arms for long periods of time in individuals presenting with this phenotype has not been emphasized. METHODS: We reviewed the records of patients who had a neurogenic "man-in-the-barrel" phenotype documented by examination at least 18 months after onset. These patients had severe bilateral upper-extremity neurogenic atrophy that spared lower-extremity, respiratory, and bulbar musculature. RESULTS: Nine of 10 patients meeting these criteria had a purely lower motor neuron disorder. During follow-up periods ranging from 3 to 11 years from onset, only three patients developed lower-extremity weakness, and none developed respiratory or bulbar dysfunction or lost the ability to ambulate. CONCLUSION: Patients presenting with severe weakness that is fully isolated to the upper limbs, without pyramidal signs, may have a relatively stable variant of motor neuron disease.

Chronic cryptogenic sensory polyneuropathy: clinical and laboratory characteristics.

BACKGROUND: Chronic sensory-predominant polyneuropathy (PN) is a common clinical problem confronting neurologists. Even with modern diagnostic approaches, many of these PNs remain unclassified. OBJECTIVE: To better define the clinical and laboratory characteristics of a large group of patients with cryptogenic sensory polyneuropathy (CSPN) evaluated in 2 university-based neuromuscular clinics. DESIGN: Medical record review of patients evaluated for PN during a 2-year period. We defined CSPN on the basis of pain, numbness, and tingling in the distal extremities without symptoms of weakness. Sensory symptoms and signs had to evolve for at least 3 months in a roughly symmetrical pattern. Identifiable causes of PN were excluded by history, physical examination findings, and results of laboratory studies. We analyzed clinical and laboratory data from patients with CSPN and compared findings in patients with and without pain. RESULTS: Of 402 patients with PN, 93 (23.1%) had CSPN and stable to slowly progressive PN syndrome. These patients presented with a mean age of 63.2 years and a mean duration of symptoms of 62.9 months. Symptoms almost always started in the feet and included distal numbness or tingling in 86% of patients and pain in 72% of patients. Despite the absence of motor symptoms at presentation, results of motor nerve conduction studies were abnormal in 60% of patients, and electromyographic evidence of denervation was observed in 70% of patients. Results of laboratory studies were consistent with axonal degeneration. Patients with and without pain were similar regarding physical findings and laboratory test abnormalities. Only a few patients (<5%) had no evidence of large-fiber dysfunction on physical examination or electrophysiologic studies. All 66 patients who had follow-up examinations (mean, 12.5 months) remained ambulatory. CONCLUSIONS: Cryptogenic sensory polyneuropathy is a common, slowly progressive neuropathy that begins in late adulthood and causes limited motor impairment. Isolated small-fiber involvement is uncommon in this group of patients. Management should focus on rational pharmacotherapy of neuropathic pain combined with reassurance of CSPN's benign clinical course.

Multifocal acquired demyelinating sensory and motor neuropathy: the Lewis-Sumner syndrome.

We report 11 patients with multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy, defined clinically by a multifocal pattern of motor and sensory loss, with nerve conduction studies showing conduction block and other features of demyelination. The clinical, laboratory, and histological features of these patients were contrasted with those of 16 patients with multifocal motor neuropathy (MMN). Eighty-two percent of MADSAM neuropathy patients had elevated protein concentrations in the cerebrospinal fluid, compared with 9% of the MMN patients (P < 0.001). No MADSAM neuropathy patient had elevated anti-GM1 antibody titers, compared with 56% of MMN patients (P < 0.01). In contrast to the subtle abnormalities described for MMN, MADSAM neuropathy patients had prominent demyelination on sensory nerve biopsies. Response to intravenous immunoglobulin treatment was similar in both groups (P = 1.0). Multifocal motor neuropathy patients typically do not respond to prednisone, but 3 of 6 MADSAM neuropathy patients improved with prednisone. MADSAM neuropathy more closely resembles chronic inflammatory demyelinating polyneuropathy and probably represents an asymmetrical variant. Given their different clinical patterns and responses to treatment, it is important to distinguish between MADSAM neuropathy and MMN.

North Carolina macular dystrophy (MCDR1) locus: a fine resolution genetic map and haplotype analysis.

PURPOSE: We previously reported linkage of North Carolina macular dystrophy in a single isolated family to a broad region on chromosome 6q16. In order to refine the localization of the MCDR1 gene (North Carolina macular dystrophy), additional families with this disease and new markers were studied. METHODS: We ascertained 10 families with the North Carolina macular dystrophy phenotype (MCDR1). These families were of various ethnic and geographic origins such as Caucasian, Mayan Indian, African-American, French, British, German, and American of European decent. Two hundred thirty-two individuals in these families underwent comprehensive ophthalmic examinations and blood was collected for genotyping. One hundred seventeen were found to be affected. Linkage simulation studies were performed. Two-point linkage, haplotype analysis, and multipoint linkage was performed using VITESSE and FASTLINK. HOMOG was used to test for genetic heterogeneity. RESULTS: The clinical features were consistent with the diagnosis of North Carolina macular dystrophy in all families. Multipoint linkage analysis indicates that the MCDR1 gene is in the interval between D6D249 and D6S1671 with a maximum LOD score of 41.52. There was no evidence of genetic heterogeneity among the families studied. Families 765, 768, 772, 1193, and 1292 shared the same chromosomal haplotype in this region. CONCLUSIONS: This is the largest single data set of families with the MCDR1 phenotype. The single large family from North Carolina continues to be informative for the closest flanking markers and alone supports the minimal candidate region as suggested by previous studies. There remains no evidence of genetic heterogeneity in this disease. Most of the American families appear to have descended from the same ancestral mutation. The remaining families could each represent independent origins of the mutation in the MCDR1 gene.

Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy.

Acute and chronic inflammatory demyelinating polyneuropathies represent an important group of disorders. Although the acute form is more common, all clinical neurologists will eventually encounter patients with these disorders. Acute inflammatory demyelinating polyneuropathy, or Guillain-Barré syndrome, is the most common cause of acute generalized weakness. Chronic inflammatory demyelinating polyneuropathy, characterized by progressive or relapsing weakness, is important to recognize because it represents a significant number of all initially undiagnosed acquired neuropathies. There are a variety of reasonable therapies available for both of these acquired demyelinating neuropathies. Recently much has been learned about pathogenesis and treatment. This review describes the clinical presentations, laboratory studies, diagnostic criteria, treatment, and prognosis for each disorder.