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Introduction and Background: Adherence is a critical factor for optimal clinical outcomes in multiple sclerosis (MS) treatment. This study investigated the adherence and clinical outcomes of MS patients treated with subcutaneous (sc) interferon (IFN) (β)-1a, an established immunomodulatory treatment for relapsing MS. The benefits of a patient support programme (PSP) were also studied., Methods: This phase-IV prospective, observational multicentre study enrolled patients with relapsing MS who were treated with sc IFN β-1a for 24 months was conducted at 53 centres across 17 countries. The primary endpoint was adherence to sc IFN β-1a treatment, as assessed using Morisky Green Levine Medication Adherence Scale (MGLS) scores at 24 months. The MGLS is a self-reported diagnostic tool to address medication non-adherence, with a score ranging from 0 to 4, with 0 representing high adherence, 1-2 representing medium adherence, and 3-4 representing low adherence. Other endpoints included time to study and treatment discontinuation over 24 months, the proportion of relapse-free patients, and Expanded Disability Status Scale (EDSS) progression (defined as ≥1.0 point increase sustained for 3 months) at 24 months. A subgroup analysis was performed for endpoints based on patients assigned to PSP (yes/no-PSP versus non-PSP subgroup)., Results: Of the 577 patients enrolled, 408 had evaluable MGLS scores at 24 months. A total of 336 (58.2%; 95% confidence interval [CI]: 54.1-62.3%) patients reported high adherence, 57 (9.9%; 95% CIs: 7.6-12.7%) reported medium adherence, and 15 (2.6%; 95% CI: 1.5-4.3%) reported low adherence at 24 months. The PSP subgroup reported higher adherence (n = 206; 65.8%) than the non-PSP subgroup (n = 130; 56.5%). By 24 months, 52.2% of the patients were relapse-free and 17.2% patients experienced ≥1 relapse. Expanded Disability Status Scale progression was observed in 12.3% of patients. Over the 24-month period, 30.8% of the patients discontinued treatment, and the most common reasons for treatment discontinuation were adverse events (AEs, 10.4%), being lost to followup (7.1%), and a lack of efficacy (5.5%). Overall, 39.6% patients experienced ≥1 AE, which ranged from mild to moderate., Conclusion: The study demonstrated high adherence to sc IFN β-1a treatment with an added benefit of PSP participation. More than half of the patients remained relapse-free over a 24-month period. No new safety concerns to sc IFN β-1a treatment were observed., Clinical Trial Registration: https://clinicaltrials.gov/study/NCT02921035, NCT02921035., Competing Interests: RA-R reports receiving personal compensation for serving on speaker/advisory boards for Bayer, Biogen, Merck, Novartis, Roche, and Sanofi, and receiving research support from Biogen, Merck, Novartis, and Roche for the establishment of regional multiple sclerosis registries and the conduct of clinical trials. MZ has received fees for advisory boards and lectures from Merck, Biogen, Roche, Sanofi, Bayer and Novartis. EC has received speaker honoraria from Novartis, Biogen, Sanofi, and Merck and travel support from Novartis, Biogen, Sanofi, and Merck. KT is an employee of Merck Serono Middle East FZ-Ltd., Dubai, UAE, an affiliate of Merck KGaA., (Copyright © 2023 Al-Roughani, Zakaria, Cupler and Taha.)

This article focuses on the diagnosis and management of neuromyelitis optica spectrum disorder (NMOSD). NMOSD is an autoimmune, demyelinating condition characterized by inflammation of the optic nerve and/or the spinal cord, with symptoms that can range from mild impairment of movement to paralysis. The newly approved diagnostic criteria have improved the accuracy of NMOSD diagnosis. The management of NMOSD is under major revolution due to the many new therapeutic options. The role of the antibodies directed at aquaporin-4 (AQP4) has materialized as a biomarker for NMOSD. Several new treatments that target variable aspects in immunopathology such as IL-6, complement, or depletion of B cells are emerging. The management of AQP4-negative patients remains challenging., (Copyright © 2022. Published by Elsevier B.V.)

Multiple sclerosis (MS) most commonly presents in young adults, although 3-5% of patients develop MS prior to the age of 18 years. The new and comprehensive consensus for the management of MS in Saudi Arabia includes recommendations for the management of MS and other CNS inflammatory demyelinating disorders in pediatric and adolescent patients. This article summarizes the key recommendations for the diagnosis and management of these disorders in young patients. Pediatric and adult populations with MS differ in their presentation and clinical course. Careful differential diagnosis is important to exclude alternative diagnoses such as acute disseminated encephalomyelitis (ADEM) or neuromyelitis optica spectrum disorders (NMOSD). The diagnosis of MS in a pediatric/adolescent patient is based on the 2017 McDonald diagnostic criteria, as in adults, once the possibility of ADEM or NMOSD has been ruled out. Few data are available from randomized trials to support the use of a specific disease-modifying therapy (DMT) in this population. Interferons and glatiramer acetate are preferred initial choices for DMTs based on observational evidence, with the requirement of a switch to a more effective DMT if breakthrough MS activity occurs., Competing Interests: Declaration of Competing Interest Authors deny any conflict of interest., (Copyright © 2022. Published by Elsevier B.V.)

This systematic review and meta-analysis aimed to identify deferentially expressed serum miRNAs in multiple sclerosis patients and to evaluate their diagnostic value in multiple sclerosis diagnosis. Studies were identified on PubMed, Google scholar and Saudi digital library up to 30 September 2019. Articles that examined miRNA expression level in MS patients compared to healthy control group were included in the review and the data were extracted by three independent author. The comprehensive Meta-Analysis version 3 software was used for meta-analysis and heterogeneity of studies was identified according to I2 value. Our literatures search identified 9 eligible articles concerning the serum miRNA as a diagnostic biomarker for multiple sclerosis in comparison to healthy control group. 19 serum miRNAs differentially expressed in MS patients were identified (8 downregulated, 11 upregulated and 1 with discordant result). In publications that provided information on specific miRNA diagnostic value, the pooled AUC was 72% (95% CI 0.65-0.78, p -value 0.00) for the overall multiple sclerosis patients and primary progressive MS (PPMS) (95% CI 0.66-0.78 p -value 0.00). A miRNA panel of four miRNAs showed high sensitivity (73%) and specificity (68%) in distinguishing multiple sclerosis from control groups. When using single miRNA (miR-145), the sensitivity increased to 79% and the specificity to 87%. The available data from the literature and this meta-analysis suggests the potential use of serum miRNA as biomarkers for early diagnosis of MS with high sensitivity and specificity in distinguishing multiple sclerosis subtypes from healthy controls. Abbreviation : MS: Multiple sclerosis; IDD: inflammatory demyelinating diseases; RRMS: relapsing-remitting Multiple sclerosis; PPMS: primary progressive Multiple sclerosis; SPMS: secondary progressive Multiple sclerosis; NMO: Neuromyelitis optica; miRNA: microRNA; ECmiRNA: extracellular microRNA; AUC: Area Under the Curve; ROC: Receiver Operator Characteristic.

Background: The prevalence of multiple sclerosis (MS) is increasing in Gulf Cooperation Council (GCC) countries. Multiple sclerosis contributes to significant burden on patients and caregivers. The pharmacological treatment in MS involves treating acute exacerbations and preventing relapses and disability progression using disease-modifying therapies. Clinical evidence suggests that teriflunomide is one of the therapeutic choices for patients with relapsing-remitting MS (RRMS). However, genetic and cultural differences across different regions may contribute to variations in drug use. Therefore, it is necessary to consider real-world evidence for teriflunomide usage in GCC countries., Methods: An expert group for MS gathered from GCC countries in December 2020. The consensus highlighting role of teriflunomide in MS management has been developed using clinical experiences and evidence-based approach., Results: The expert-recommended patient profile for teriflunomide usage includes individuals aged 18 years and above, both men and women (on effective contraceptives) with clinically isolated syndrome or RRMS. The factors considered were cost-effectiveness of the drug, patient preference, adherence, monitoring, established safety profile, and coronavirus disease 2019 status., Conclusion: Expert recommendations based on their clinical experience will be more helpful to clinicians in clinical settings regarding the usage of teriflunomide and provide valuable insights applicable in day-to-day practice., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Pompe disease is a rare, metabolic, autosomal recessive disorder. Early diagnosis is critical for progressive Pompe disease as delays can significantly alter the clinical course of the disease. Diagnostic modalities, including dried blood spot testing and genetic testing, are available and are effective for diagnosing patients with late-onset Pompe disease (LOPD). However, clinicians face numerous clinical challenges related to the diagnosis of the disease. Two expert group committee meetings, involving 11 experts from the United Arab Emirates, Kuwait, the Kingdom of Saudi Arabia, and Oman, were convened in October 2019 and November 2020 respectively to develop a uniform diagnostic algorithm for the diagnosis of pediatric and adult LOPD in the Arabian Peninsula region. During the first meeting, the specialty-specific clinical presentation of LOPD was defined. During the second meeting, a diagnostic algorithm was developed after a thorough validation of clinical presentation or symptoms, which was performed with the aid of existing literature and expert judgement. A consensus was reached on the diagnostic algorithm for field specialists, such as neurologists, rheumatologists, general practitioners/internal medicine specialists, orthopedic specialists, and pulmonologists. This specialty-specific diagnostic referral algorithm for pediatric and adult LOPD will guide clinicians in the differential diagnosis of LOPD.

Disease-modifying therapies (DMT) for relapsing-remitting MS (RRMS) act on the immune system, suggesting a need for caution during the SARS-CoV2/Covid-19 pandemic. A group of experts in MS care from Saudi Arabia convened to consider the impact of Covid-19 on MS care in that country, and to develop consensus recommendations on the current application of DMT therapy. Covid-19 has led to disruption to the care of MS in Saudi Arabia as elsewhere. The Expert Panel considered a DMT's overall tolerability/safety profile to be the most important consideration on whether or not to prescribe at this time. Treatment can be started or continued with interferon beta, teriflunomide, dimethyl fumarate, or natalizumab, as these DMTs are not associated with increased risk of infection (there was no consensus on the initiation of other DMTs). A consensus also supported continuing treatment regimens with fingolimod (or siponimod) and cladribine tablets for a patient without active Covid-19. No DMT should be imitated in a patient with active Covid-19, and (only) interferon beta could be continued in the case of Covid-19 infection. Vaccination against Covid-19 is a therapeutic priority for people with MS. New treatment should be delayed for 2-4 weeks for vaccination. Where treatment is already ongoing, vaccination against Covid-19 should be administered immediately without disruption of treatment (first-line DMTs, natalizumab, fingolimod), when lymphocytes have recovered sufficiently (cladribine tablets, alemtuzumab) or 4 months after the last dose (ocrelizumab). These recommendations will need to be refined and updated as new clinical evidence in this area emerges., (Copyright © 2021. Published by Elsevier B.V.)

More than half of all patients with multiple sclerosis (MS) in the Kingdom of Saudi Arabia (KSA) are women of childbearing age. Raising a family is an important life goal for women in our region of the world. However, fears and misconceptions about the clinical course of relapsing-remitting MS (RRMS) and the effects of disease-modifying drugs (DMDs) on the foetus have led many women to reduce their expectations of raising a family, sometimes even to the point of avoiding pregnancy altogether. The increase in the number of DMDs available to manage RRMS and recent studies on their effects in pregnancy have broadened management options for these women. Interferon beta now has an indication in Europe for use during pregnancy (according to clinical need) and can be used during breastfeeding. Glatiramer acetate is a further possible option for women with lower levels of RRMS disease activity who are, or about to become, pregnant; natalizumab may be used up to 30 weeks in patients with higher levels of disease activity. Where possible, physicians need to support and encourage women to pursue their dream of a fulfilling family life, supported where necessary by active interventions for RRMS that are increasingly evidence based., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Mohammed Al Jumah et al.)

Introduction: ADCY5-related hyperkinesia encompasses a heterogeneous group of phenotypes, including paroxysmal chorea, myoclonus, and dystonia. The disease is attributed to mutations of ADCY5, which encodes an adenylate cyclase enzyme. The disease can occur in a sporadic or familial pattern. With exception of one study, all reports on familial ADCY5-related hyperkinesia were associated with an autosomal dominant inheritance. Herein, we describe a native Arabian Bedouin family with an autosomal recessive ADCY5-related disorder and expand the genotypic and phenotypic spectrum of this disorder., Methods: The pedigree included 4 generations of a family with 6 affected individuals. The patients were examined clinically and radiologically. Homozygosity mapping and Whole Exome Sequencing (WES) were used to identify a variant, predicted to be pathogenic, which segregated with disease in this family., Results: All patients presented with early-onset dystonia and myoclonus. The patients had delayed motor and language milestones, axial hypotonia, severe anxiety, social phobia, and isolation. One patient had dilated cardiomyopathy. WES of one affected individual revealed a novel homozygous missense mutation (c.1762G > A, p.D588N) of ADCY5, that segregated with disease in an autosomal recessive manner, and was absent in more than 1000 ethnically-matched chromosomes. The mutation replaces a highly conserved nucleotide and is predicted to be deleterious., Conclusion: This study reports the second family with autosomal recessive childhood-onset ADCY5-related disorder and expands our understanding of phenotype/genotype correlations of this disorder., (Copyright © 2019. Published by Elsevier Ltd.)

Objective: Electroencephalography (EEG) in the intensive care unit (ICU) is often done to detect non-convulsive seizures (NCS). The outcome of ICU patients with NCS strongly depends on the underlying etiology. The implication of NCS and other EEG findings on clinical outcome independent from their etiology is not well understood and our aim to investigate it., Patients and Methods: We retrospectively identified all adult patients in the ICU who underwent EEG monitoring between January 2008 and December 2011. The main goals were to define the rate of NCS or non-convulsive status epilepticus (NCSE) occurrence in our center among patients who underwent EEG monitoring and to examine if NCS/NCSE are associated with poor outcome [defined as death or dependence] with and without adjustment for underlying etiology. The rate of poor outcome among different EEG categories were also investigated., Results: During the study period, 177 patients underwent EEG monitoring in our ICU. The overall outcome was poor in 62.7% of those undergoing EEG. The rate of occurrence of NCS/NCSE was 8.5% and was associated with poor outcome in 86.7% with an odds ratio (OR) of 5.1 (95% confidence interval [CI] 1.09-23.8). This association was maintained after adjusting for underlying etiologies with OR 5.6 (95% CI 1.05-29.6). The rate of poor outcome was high in the presence of periodic discharges and sharp and slow waves of 75% and 61.5%, respectively., Conclusions: Our cohort of ICU patients undergoing EEGs had a poor outcome. Those who developed NCS/NCSE experienced an even worse outcome regardless of the underlying etiology., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Pompe disease is a rare autosomal recessive disorder caused by a deficiency of the lysosomal enzyme alpha-glucosidase responsible for degrading glycogen. Late-onset Pompe disease has a complex multisystem phenotype characterized by a range of symptoms., Methods: An expert panel from the Middle East and North Africa (MENA) region met to create consensus-based guidelines for the diagnosis and treatment of late-onset Pompe disease for the MENA region, where the relative prevalence of Pompe disease is thought to be high but there is a lack of awareness and diagnostic facilities., Results: These guidelines set out practical recommendations and include algorithms for the diagnosis and treatment of late-onset Pompe disease. They detail the ideal diagnostic workup, indicate the patients in whom enzyme replacement therapy should be initiated, and provide guidance on appropriate patient monitoring., Conclusions: These guidelines will serve to increase awareness of the condition, optimize patient diagnosis and treatment, reduce disease burden, and improve patient outcomes.

Introduction: Pompe disease is a rare, autosomal recessive disorder caused by deficiency of the glycogen-degrading lysosomal enzyme acid alpha-glucosidase. Late-onset Pompe disease is a multisystem condition, with a heterogeneous clinical presentation that mimics other neuromuscular disorders., Methods: Objective is to propose consensus-based treatment and management recommendations for late-onset Pompe disease., Methods: A systematic review of the literature by a panel of specialists with expertise in Pompe disease was undertaken., Conclusions: A multidisciplinary team should be involved to properly treat the pulmonary, neuromuscular, orthopedic, and gastrointestinal elements of late-onset Pompe disease. Presymptomatic patients with subtle objective signs of Pompe disease (and patients symptomatic at diagnosis) should begin treatment with enzyme replacement therapy (ERT) immediately; presymptomatic patients without symptoms or signs should be observed without use of ERT. After 1 year of ERT, patients' condition should be reevaluated to determine whether ERT should be continued., (Copyright © 2011 Wiley Periodicals, Inc.)

Anterior interosseous nerve syndrome (AINS) has not been widely recognized as a possible complication following peripheral catheterization. Herein we present a retrospective review of patients with AINS over the last 5 years. Six cases were identified, 4 associated with catheterization. AINS may be a rare complication of catheterization. Magnetic resonance imaging (MRI) may serve as an adjunct diagnostic modality to conventional electromyography (EMG) and nerve conduction studies, especially in patients who are intolerant of pain., (Copyright © 2011 Wiley Periodicals, Inc.)

Forty percent to 50% of acetylcholine receptor antibody-seronegative patients with myasthenia gravis have muscle-specific receptor tyrosine kinase antibodies. Many muscle-specific receptor tyrosine kinase + myasthenia gravis patients remain refractory with conventional therapies. Rituximab is an anti-CD20 monoclonal antibody used in refractory B-cell disorders. Currently there is no standard dosing schedule for rituximab. We present two muscle-specific receptor tyrosine kinase + myasthenia gravis patients clinically refractory to conventional therapy who, after a single course of rituximab, became asymptomatic and discontinued all medication.

Nephrogenic systemic fibrosis is primarily a skin disorder associated with renal insufficiency and exposure to gadolinium-containing (GAD+) contrast. We present the case of a 64-year-old man who was exposed to gadolinium while in acute renal failure, and months later developed limb stiffness, proximal weakness, and woody muscle texture. Muscle biopsy demonstrated chronic non-inflammatory fibrosing myopathy. CD34+ fibroblasts have previously been reported to be specific for nephrogenic systemic fibrosis dermopathy, and we found these in fibrotic areas of muscle and fascia. Nephrogenic systemic fibrosis is an emerging disorder, and our case highlights that it may present as a progressive myopathy with minimal skin findings.

Macrophagic myofasciitis is a novel, "inflammatory myopathy" described after a variety of vaccinations, almost exclusively in adults. We examined the relevance of histological findings of this myopathy to the clinical presentation in pediatric patients. Muscle biopsies from 8 children (7 months to 6 years old) with histological features of macrophagic myofasciitis were reviewed and correlated with the clinical manifestations. Patients underwent quadriceps muscle biopsy for suspected mitochondrial disease (4 patients), spinal muscular atrophy (2 patients), myoglobinuria (1 patient), and hypotonia with motor delay (1 patient). All biopsies showed identical granulomas composed of periodic acid-Schiff-positive and CD68-positive macrophages. Characteristic aluminum hydroxide crystals were identified by electron microscopy in 2 cases. The biopsy established diagnoses other than macrophagic myofasciitis in 5 patients: spinal muscular atrophy (2), Duchenne muscular dystrophy (1), phospho-glycerate kinase deficiency (1), and cytochrome c oxidase deficiency (1). Three children with manifestations and/or a family history of mitochondrial disease had otherwise morphologically normal muscle. All children had routine vaccinations between 2 months and 1 year before the biopsy, with up to 11 intramuscular injections, including the biopsy sites. There was no correlation between histological findings of macrophagic myofasciitis in biopsies and the clinical symptoms. We believe that macrophagic myofasciitis represents a localized histological hallmark of previous immunization with the aluminum hydroxide adjuvants contained in vaccines, rather than a primary or distinct inflammatory muscle disease.

Tuberculosis (TB) of the central nervous system (CNS) is still prevalent in many developing countries. Tuberculoma is always considered in the differential diagnosis of enhancing intra-axial lesions of the brain. Brain tuberculomas can present in many different clinical and radiological patterns, disseminated or miliary brain tuberculomas are very rare. We describe the case of a 25-year-old immunocompetent female with miliary brain tuberculomas. She presented with a history of progressive headache and unsteady gait. Serial Magnetic resonance imaging (MRI) studies revealed growing, multiple small enhancing lesions in the brain, most lesions measured approximately 2mm in diameter, in both the supratentorial and infratentorial compartments. Her investigation failed to reveal any evidence of TB outside the CNS. Open biopsy revealed multiple caseating granulomas and mycobacterin tuberculosis was cultured. She improved clinically and radiologically after starting anti-tuberculous pharmacotherapy. The clinical course, radiological images and pathological studies of this patient are presented. In conclusion miliary brain tuberculomas are rare and unique clinical and radiological entity. It may affect immunocompetent individuals with no other signs of other systemic involvement.

Objective: To identify the gene and specific mutation underlying hyaline body myopathy in the family studied., Methods: A microsatellite-based whole genome scan was performed. Linkage analysis assumed autosomal dominant inheritance and equal allele frequencies. A candidate gene approach within the linked interval and direct sequencing were used for mutation detection., Results: Initial analysis indicated a maximum lod score of 3.01 at D14S1280. High-density mapping surrounding the linked locus was performed. Multipoint analysis showed that the linked region with a maximum lod score of 3.01 extended from D14S742 to D14S608 with a peak non-parametric linkage (NPL) score of 3.75 at D14S608. The myosin heavy chain genes MYH6 and MYH7 map to the region between D14S742 and D14S1280. Sequence analysis of the coding regions of MYH7 revealed an A-->T transversion at nucleotide position 25596 (M57965) resulting in a histidine-to-leucine amino acid change at residue 1904 (H1904L)., Conclusion: Pathogenicity of the MYH7 H1904L mutation most likely results from disruption of myosin heavy chain assembly or stability of the sarcomeric protein. The MYH7 tail domain mutation results in an inclusion body myopathy with an apparent absence of hypertrophic cardiomyopathy usually associated with mutations of this gene.

Objective: To report clinical, morphologic, and immunohistochemical studies on autosomal dominant, clinically nonprogressive, and not previously described progressive forms of hyaline body (HB) myopathy (HBM) in a Saudi Arabian kindred., Results: Muscle biopsies from four patients showed HB in type 1 fibers; they were positive for ATPase at pH 4.3/4.6 and for heavy chain slow myosin (HCSM); some HB were HCSM negative. HB were nonreactive for alphaB-crystallin, ubiquitin, tropomyosin, actins, desmin, and components of sarcolemma. Ultrastructurally, HB were granular and filamentous or amorphous, often with fragments of sarcomeres, and surrounded by a zone of sarcomeric disorganization. All biopsies showed "myopathic" changes, angulated neurogenic fibers, and fiber type grouping. There was no correlation between HB and course of disease; the progressive cases displayed more severe myopathic features., Conclusions: Formation of hyaline bodies in hyaline body myopathy is associated with either myolysis or defective incorporation of heavy chain slow myosin into the cytoskeleton. Hyaline bodies very likely contain additional unidentified proteins. Neurogenic factors are also involved in the hyaline body myopathy pathogenesis.

Objective: To determine the usefulness of cerebrospinal fluid tests in the diagnosis of neurosyphilis., Methods: Two hundred and seven cerebrospinal fluid-Venereal Disease Research Laboratories tests were performed at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia between 1992 and 1997. The records of 14 cases with progressive neurological disease and reactive serum fluorescent treponemal absorbent antibodies or treponemal pallidum hemagglutination test were reviewed for clinical presentation, cerebrospinal fluid analysis and Venereal Disease Research Laboratories, neuro-imaging abnormalities and compatibility with the diagnosis of neurosyphilis. The diagnosis of neurosyphilis was made if the patient had reactive serum fluorescent treponemal absorbent antibodies or treponemal pallidum hemagglutination, history of progressive neurological disease and increased cerebrospinal fluid cells or protein., Results: None of the 207 cerebrospinal fluid-Venereal Disease Research Laboratories tests were reactive. The diagnosis of neurosyphilis was made in 10 out of 14 cases with progressive neurological disease and reactive serum rapid plasma reagin, fluorescent treponemal absorbent antibodies and treponemal pallidum hemagglutination., Conclusion: We conclude that if reactive cerebrospinal fluid-Venereal Disease Research Laboratories is required to confirm or diagnose neurosyphilis, most cases will be overlooked.

Objective: To determine the usefulness of cerebrospinal fluid tests in the diagnosis of neurosyphilis., Methods: Two hundred and seven cerebrospinal fluid-Venereal Disease Research Laboratories tests were performed at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia between 1992 and 1997. The records of 14 cases with progressive neurological disease and reactive serum fluorescent treponemal absorbent antibodies or treponemal pallidum hemagglutination test were reviewed for clinical presentation, cerebrospinal fluid analysis and Venereal Disease Research Laboratories, neuro-imaging abnormalities and compatibility with the diagnosis of neurosyphilis. The diagnosis of neurosyphilis was made if the patient had reactive serum fluorescent treponemal absorbent antibodies or treponemal pallidum hemagglutination, history of progressive neurological disease and increased cerebrospinal fluid cells or protein., Results: None of the 207 cerebrospinal fluid-Venereal Disease Research Laboratories tests were reactive. The diagnosis of neurosyphilis was made in 10 out of 14 cases with progressive neurological disease and reactive serum rapid plasma reagin, luorescent treponemal absorbent-absorbent antibodies and treponemal pallidum hemagglutination., Conclusion: We conclude that if reactive cerebrospinal fluid-Venereal Disease Research Laboratories is required to confirm or diagnose neurosyphilis, most cases will be overlooked.

Neurotrophin 4/5 (NT4/5) is the least understood member of the mammalian neurotrophin family. Precise and reliable determinations of endogenous NT4/5 levels are essential to understand its physiology. Immunoassay has been used for neurotrophin quantification for over three decades. However, this apparently simple task has proved elusive: conflicting results have long been recognized for nerve growth factor (NGF; up to 10000-fold variations in serum values have been reported in the literature) and more recently, for brain-derived neurotrophic factor (as much as 50-fold reported in rat hippocampus). Reasons for these variations have been extensively investigated by researchers, but rarely explained. During the development of our NT4/5 immunoassay, we discovered that false positive reactions resulted when tissues were extracted and assayed under certain conditions. In this study, we examined the major factors that adversely affect the quantification of NT4/5. Tissue samples from Sprague-Dawley rats were dissected and extracted in a range of buffers. The assay was performed on 96 well vinyl plates using sheep anti-NT4/5 immunoglobulin (Ig) as the capture (first) antibody, and a monoclonal anti-NT4/5 as the detector (second) antibody, followed by anti-mouse IgG (third) conjugated with peroxidase or alkaline phosphatase from several manufacturers. Our results show that: (1) tissue extraction at high or low pH, a method previously found to increase the measurable amount of NGF, produced greater false positive results for NT4/5 when compared with extraction at neutral pH; (2) the most significant source of error derived from the use of conjugated antibodies capable of reacting with molecules within tissue extracts which bind to the plate, even after thorough blocking; and (3) quantification is also significantly affected by both the standards used and the ability of the antibodies to react with these standards. Our findings indicate that the precise determination of neurotrophin levels requires quality reagents and the optimization of extraction conditions for each neurotrophin. The use of a two - rather than a three - antibody assay system avoids most of the interactions which give rise to false positive reactions.

Miyoshi myopathy (MM) is a rare autosomal recessive distal myopathy linked to chromosome 2p12-14 that has not been described in Saudi Arabia. A Saudi family with five siblings aged 3-25 years, an unrelated 18-year-old woman and a 40-year-old man with MM were identified. All patients underwent a neurological examination, serum chemistry, electromyography and MRI of the legs. Four patients underwent a muscle biopsy that was processed for routine enzyme histochemistry and immunocytochemical analyses for dystrophin and adhalin (alpha-sarcoglycan). The two sporadic and two familial cases showed classic findings of MM, including early adult onset, preferential involvement of gastrocnemius muscles, markedly elevated serum creatine kinase levels and dystrophic-appearing muscle without vacuoles. Magnetic resonance imaging revealed selective involvement of the posterior compartment muscles and myoedema by STIR sequences. The remaining three familial cases had elevated serum creatine kinase levels and two also had early myopathic findings by EMG suggestive of MM.

Sporadic inclusion body myositis (IBM) is the most common inflammatory myopathy affecting patients over the age of 50 years. Dysimmune and degenerative aetiologies have been postulated, but viral infections have not been associated with the disease. Two HIV-I (human immunodeficiency virus type 1) infected men and one woman infected with HTLV-1 (human T cell leukaemia virus type 1) developed progressive proximal muscle weakness unrelated to antiretroviral therapy. Their muscle biopsies were studied by light and electron microscopy, by immunocytochemistry to determine the expression of major histocompatibility complex (MHC) molecules and identify the type of infiltrating cells and T cell receptor (TCR) subunits, and by reverse transcription-polymerase chain reaction (RT-PCR) and single or double immunocytochemistry to search for retrovirally infected endomysial cells. The clinical features were consistent with sporadic IBM. The muscle biopsies showed primary endomysial inflammation, red-rimmed vacuoles, amyloid deposits, eosinophilic inclusions, and small round fibres in groups, all diagnostic of IBM. The muscle fibres expressed MHC class-1 antigens and were invaded primarily by CD8+ T-lymphocytes preferentially bearing TCR V beta 5.1 and V beta 13 chains. The HIV-1 or HTLV-1 antigens were detected only on endomysial macrophages on or around muscle fibres, but not within the muscle fibres. We conclude that IBM occurs in HIV-1 and HTLV-1 infected individuals and has a clinical, histological and immunological pattern identical to sporadic IBM in the non-retrovirally infected patients. Retroviruses do not directly infect the muscle, but persistent retroviral infections may provide superantigenic stimulation and trigger an endomysial inflammatory response identical to that occurring in sporadic IBM.

Peripheral neuropathies represent the most common neurological manifestation in patients infected with HIV infection occurring either early in the infection or during the course of the illness. They present as acute or chronic demyelinating neuropathies (Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy), mononeuritis multiplex, ganglioneuronitis, cytomegalovirus-related polyradiculoneuropathy, autonomic neuropathy or distal painful sensory neuropathy. They are multifactorial in aetiology. Their putative cause (viral, autoimmune, toxic, nutritional, co-infections) are often dictated by the stage of the underlying HIV disease. The virus, which is not found within ganglionic neurones or Schwann cells but only within the endoneurial macrophages, may generate a tissue-specific autoimmune attack by secretion of cytokines that promote trafficking of activated T cells and macrophages within the endoneurial parenchyma. The wide use of the neurotoxic antiretroviral nucleoside analogues ddC, ddI, d4T and 3TC, exacerbate or trigger subclinical neuropathy in many of these patients.

Zidovudine-induced myopathy is characterized by reversible muscle weakness, wasting, myalgia, fatigue, and elevated creatine kinase (CK). Some zidovudine-treated patients with normal muscle strength experience excessive fatigue, myalgia, or transient mild CK elevations that improve when zidovudine is stopped. To determine the cause of these symptoms, we studied 13 physically fit, HIV-infected men who developed fatigue, myalgia, and reduced endurance, while taking zidovudine for a mean period of 20 months (2-39 months), with neurological evaluation and muscle biopsy processed for enzyme histochemistry and electron microscopy (EM). All subjects had normal muscle strength. In 6 of the 13 patients, muscle biopsies were normal by enzyme histochemistry. EM, however, demonstrated proliferation of normal or abnormal mitochondria, and increased amounts of lipid, glycogen, and lipofuscin. Electromyographic (EMG) studies (5/5) and serum CK (6/6) were normal. The other 7 individuals had signs of moderate to severe mitochondrial abnormalities shown by both light microscopy and EM, characterized by severe destruction, vacuolization, and rare paracrystalline inclusions. Most had elevated CK (4 out of 7) and normal EMG (5 out of 7). The severity of morphological abnormalities did not correlate with duration of HIV infection, zidovudine therapy, or zidovudine dosage. We conclude that in zidovudine-treated patients, symptoms of fatigue, myalgia, reduced endurance, and exercise intolerance represent early signs of zidovudine-induced mitochondriotoxicity, which causes an energy shortage within the muscle fibers even when muscle strength is still normal. Zidovudine, a DNA chain terminator, results in overt myopathy when a critical threshold of molecular, histological, and biochemical dysfunction of mitochondria is crossed, which seems to vary between individuals.

Objective: To determine if high-dose intravenous immunoglobulin therapy is effective in improving muscle strength or in arresting the pace of disease progression in patients with rapidly progressive amyotrophic lateral sclerosis., Design: An open-label pilot study of intravenous infusions of high-dose immunoglobulin administered once a month for 3 months in nine patients with classic amyotrophic lateral sclerosis. Selected patients had a rapidly progressive course with signs of worsening noticeably evident every 6 weeks prior to therapy. A patient with multifocal motor neuropathy with conduction block that presented as a lower motor neuron syndrome was concurrently treated to document the efficacy of the same preparation of immunoglobulin in a potentially treatable disease that simulates lower motor neuron syndrome. The efficacy of high-dose intravenous immunoglobulin infusions was assessed by objective measurement of maximum voluntary isometric contraction in all muscle groups of two limbs before and after therapy., Setting: The Clinical Center of the National Institutes of Health, Bethesda, Md., Results: All patients with amyotrophic lateral sclerosis worsened during the study. By the end of the third month, their mean total muscle scores (megascores) had declined by 71.2 points, from a mean of 369.7 (range, 200 to 605) to 298.5 (range, 130 to 552) points. The pace of progression did not change during the 4-month observation period. In contrast, the patient with multifocal motor neuropathy responded to intravenous immunoglobulin therapy and increased his megascores by 146 points after 3 months. The GM1 antibody titers were normal in all the patients., Conclusions: High-dose intravenous immunoglobulin, a prohibitively expensive drug, has no apparent therapeutic role in improving the symptoms or arresting the pace of progression in patients with amyotrophic lateral sclerosis. In contrast, multifocal motor neuropathy is an immunopathologically different disease that responds to intravenous immunoglobulin therapy.

Objective: Intravenous immunoglobulin is widely used to treat various autoimmune disorders. After observing instances of aseptic meningitis in treated patients, we studied the frequency and associated risk factors for aseptic meningitis in patients treated with high-dose intravenous immunoglobulin., Design: Retrospective analysis of a prospective cohort study., Setting: Tertiary research referral center., Patients: 54 consecutive patients with various immune-related neuromuscular diseases participating in ongoing therapeutic trials of high-dose (2 g/kg) intravenous immunoglobulin., Measurements: Analysis of patient records for evidence of aseptic meningitis, associated risk factors, penetration of serum IgG into the cerebrospinal fluid, and clearance of cerebrospinal fluid IgG., Results: Of 54 patients, 6 (11%; 95% CI, 4% to 23%) developed aseptic meningitis within 24 hours after completion of the infusions. Symptoms, lasting 3 to 5 days, included severe headache, meningismus, photophobia, and fever. Cerebrospinal fluid showed pleocytosis in 4 patients (leukocyte count as high as 1169 x 10(6)/L in one patient), eosinophilia in 3 patients, and IgG elevation in all patients (as great as 7 times the upper limit of normal in one patient). Repeat cerebrospinal fluid and serum studies after 24 hours showed a 46% cerebrospinal fluid IgG clearance compared with an 11% clearance of serum IgG in one patient. Cerebrospinal fluid cultures were negative. Aseptic meningitis developed in 4 of 8 patients (50%; CI, 16% to 84%) with a history of migraine but in only 2 of 46 (4%; CI, 0.5% to 15%) patients without such a history (P = 0.003). Aseptic meningitis recurred in patients who had migraine despite the use of different commercial intravenous immunoglobulin preparations and slower rates of infusion., Conclusion: Aseptic meningitis develops in patients receiving high-dose intravenous immunoglobulin therapy. Patients with a history of migraine are more likely to develop aseptic meningitis while receiving intravenous immunoglobulin therapy, regardless of the type of commercial preparation or the infusion rate. Possible inciting factors include the IgG itself, various stabilizing products within each of the preparations, cytokine release triggered by the therapy, or cerebrovascular sensitivity in migraineurs.