Intervening to reduce the risk of future disability from multiple sclerosis: are we there yet?

Disease-modifying therapies (DMTs) delay or may prevent the progression of patients with high-risk clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (MS), and from relapsing-remitting MS to secondary progressive MS. Current evidence on the effects of DMT on disability in MS is supported by the use of the Expanded Disability Status Scale (EDSS), which is dominated by ambulation, and usually used as a secondary outcome measure. Less is known about the long-term effects of DMTs on other aspects of functional status, particularly cognition, which is a key determinant of ability to work. The time scale for measurements of disability is at most a few years, with scant data from more than 10 years of observation. Longer prospective follow-up of large numbers of patients with CIS is needed to determine whether early intervention with a DMT influences long-term disease progression. Finally, the emergence of the radiologically isolated syndrome (RIS) as a clinical entity has shifted the debate about when to intervene to an even earlier time frame. Balancing the significant side-effects associated with DMT in general and the expected outcome of pharmacologic intervention is increasingly problematic for managing patients with uncertain prognosis, as many patients may have low-risk CIS, benign MS or patients with RIS only. Preventing long-term disability in MS should be recognised more clearly as an important outcome in its own right, with disability measured more consistently with more sensitive instruments beyond the use of the EDSS.

Natalizumab treatment for multiple sclerosis: Middle East and North Africa regional recommendations for patient selection and monitoring.

BACKGROUND: Natalizumab, a highly specific α4-integrin antagonist, , has recently been registered across the Middle East and North Africa region. It improves clinical and magnetic resonance imaging (MRI) outcomes and reduces the rate of relapse and disability progression in relapsing-remitting multiple sclerosis (MS). Natalizumab is recommended for patients who fail first-line disease-modifying therapy or who have very active disease. Progressive multifocal leukoencephalopathy is a rare, serious adverse event associated with natalizumab. We aim to develop regional recommendations for the selection and monitoring of MS patients to be treated with natalizumab in order to guide local neurological societies. METHODS: After a review of available literature, a group of neurologists with expertise in the management of MS met to discuss the evidence and develop regional recommendations to guide appropriate use of natalizumab in the region. RESULTS: Disease breakthrough is defined as either clinical (relapse or disability progression) or radiological activity (new T2 lesion or gadolinium-enhancing lesions on MRI), or a combination of both. Natalizumab is recommended as an escalation therapy in patients with breakthrough disease based on its established efficacy in Phase III studies. Several factors including prior immunosuppressant therapy, anti-John Cunningham virus (JCV) antibody status and patient choice will affect the selection of natalizumab. In highly active MS, natalizumab is considered as a first-line therapy for naive patients with disabling relapses in association with MRI activity. The anti-JCV antibody test is used to assess anti-JCV antibody status and identify the risk of PML. While seronegative patients should continue treatment with natalizumab, anti-JCV antibody testing every 6 months and annual MRI scans are recommended as part of patient monitoring. In seropositive patients, the expected benefits of natalizumab treatment have to be weighed against the risks of PML. Clinical vigilance and follow-up MRI scans remain the cornerstone of monitoring. After 2 years of natalizumab therapy, monitoring should include more frequent MRI scans (every 3-4 months) for seropositive patients, and the risk-benefit ratio should be reassessed and discussed with patients. CONCLUSIONS: Recommendations have been developed to guide neurologists in the Middle East and North Africa on patient selection for natalizumab treatment and monitoring.

Characteristics of multiple sclerosis in the Middle East with special reference to the applicability of international guidelines to the region.

We have reviewed the clinical literature with reference to the local applicability of guidelines for the diagnosis and management of multiple sclerosis (MS) in the Middle East. There is a substantial burden of MS in the region: the prevalence of the disease appears to have increased markedly in recent decades, with a faster rate of increase in female vs. male patients. The aetiology and presentation of MS appears to be broadly similar in the Middle East to that in other regions. Interferon-ß is the most commonly used treatment for MS in the Middle East, as elsewhere, although it is unclear to what extent economic constraints act as a barrier to accessing this treatment. Similarly, limited available data suggest that the availability of MRI scanners appears to be lower in the Middle East than in more developed nations. Little is known concerning other potential barriers to treatment. There is a need for further research on aspects of management of MS beyond the pharmacological aspects of treatment to assess fully the potential barriers to the adoption of international guidelines for the diagnosis and management of the disease in the Middle East.

Drug-induced Parkinson`s disease. A clinical review.

Drug-induced Parkinsonism must always be suspected when parkinsonian symptom like rigidity, tremor, or postural instability appear in patients receiving drug treatment. Indeed, drug-induced Parkinsonism is a frequent etiology of secondary Parkinsonism. The main causative drugs are antipsychotic, other neuroleptic drugs, and calcium-channel entry blockers. The risk associated with antipsychotics is often dose dependent and related to dopamine D2 striatal occupancy. The risk is less for the second-generation atypical antipsychotic. The other treatments rarely involved are antidepressants, antivirals, anti-arrhythmics, lithium, valproic acid, and others. Regression of symptom will be observed in most cases after a mean delay of 3 months after cessation of treatment. In one-tenth of cases, symptoms persist after drug withdrawal leading to the diagnosis of underlined idiopathic Parkinson`s disease.

Autosomal recessive hereditary spastic paraplegia with thin corpus callosum among Saudis.

OBJECTIVE: To assess the mutational and clinical spectrum of spatacsin associated with autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC). METHODS: A retrospective study was carried out at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia from February 2008 until March 2011. Four unrelated Saudi Arabian families with ARHSP-TCC were studied, totaling 13 affected individuals. Clinical presentations included gait disturbance at variable ages (2-18 years), spastic paraplegia with mild to moderate cognitive impairment and evidence of peripheral neuropathy in 2 families. Brain MRI showed TCC accompanied by periventricular white matter changes and cortical atrophy. RESULTS: A genome wide scan demonstrated linkage to the SPG11 locus. Sequencing revealed 4 mutations. The first is an insertion/deletion (indel) consisting of a 3 base pair (bp) deletion and 23 bp insertion (L1268L fsX), the second is a one bp deletion (S1923R fsX), and the third and the fourth are nonsense mutations (Q341X and R651X). All mutations predict premature truncation of the spatacsin protein. CONCLUSION: We report 2 novel mutations in this gene, including an indel considerably larger than any other identified to date. The identification of these mutations further confirms the causative link between SPG11 and ARHSP-TCC in these families.

Clinical and molecular characterization of ataxia with oculomotor apraxia patients in Saudi Arabia.

BACKGROUND: Autosomal recessive ataxias represent a group of clinically overlapping disorders. These include ataxia with oculomotor apraxia type1 (AOA1), ataxia with oculomotor apraxia type 2 (AOA2) and ataxia-telangiectasia-like disease (ATLD). Patients are mainly characterized by cerebellar ataxia and oculomotor apraxia. Although these forms are not quite distinctive phenotypically, different genes have been linked to these disorders. Mutations in the APTX gene were reported in AOA1 patients, mutations in SETX gene were reported in patients with AOA2 and mutations in MRE11 were identified in ATLD patients. In the present study we describe in detail the clinical features and results of genetic analysis of 9 patients from 4 Saudi families with ataxia and oculomotor apraxia. METHODS: This study was conducted in the period between 2005-2010 to clinically and molecularly characterize patients with AOA phenotype. Comprehensive sequencing of all coding exons of previously reported genes related to this disorder (APTX, SETX and MRE11). RESULTS: A novel nonsense truncating mutation c.6859 C > T, R2287X in SETX gene was identified in patients from one family with AOA2. The previously reported missense mutation W210C in MRE11 gene was identified in two families with autosomal recessive ataxia and oculomotor apraxia. CONCLUSION: Mutations in APTX , SETX and MRE11 are common in patients with autosomal recessive ataxia and oculomotor apraxia. The results of the comprehensive screening of these genes in 4 Saudi families identified mutations in SETX and MRE11 genes but failed to identify mutations in APTX gene.

Cladribine Tablets and Relapsing-Remitting Multiple Sclerosis: A Pragmatic, Narrative Review of What Physicians Need to Know.

Immune reconstitution therapy (IRT) is an emerging management concept for multiple sclerosis, whereby a short course of treatment provides long-lasting suppression of disease activity. "Cladribine tablets 10 mg" refers to a total cumulative dose of cladribine given over 2 years (henceforth referred to as cladribine tablets 3.5 mg/kg); it is a relatively new treatment option that is hypothesised to act as an IRT acting preferentially on the adaptive immune system. A randomised, 2-year, placebo-controlled trial (CLARITY) showed that treatment with cladribine tablets reduced indices of disease activity (relapses, lesions on magnetic resonance images, disability progression) and that this effect outlasted the pharmacologic effect of the treatment on the immune system (mainly a reduction in circulating B and T cells, with little effect on components of the innate immune system such as monocytes). CLARITY Extension, a 2-year extension to this trial, demonstrated durable efficacy, also in patients who received the standard 2-year course of cladribine tablets 3.5 mg/kg and were re-randomised to placebo for a further 2 years. Relative risk reductions for relapse rate with cladribine tablets 3.5 mg/kg were similar for patients with or without prior high disease activity. Reductions in disability progression with cladribine tablets 3.5 mg/kg were higher in patients with prior high relapse rates with or without prior treatment non-response. In this review, we describe the therapeutic profile of cladribine tablets 3.5 mg/kg and provide practical information on initiating this treatment option in the most appropriate patients.

Autosomal recessive ADCY5-Related dystonia and myoclonus: Expanding the genetic spectrum of ADCY5-Related movement disorders.

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.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in Arabs.

OBJECTIVE: To investigate the Notch 3 mutation spectrum in Arab patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy CADASIL, which is an inherited cerebrovascular disease characterized by recurrent subcortical ischemic stroke starting in the third or fourth decade. METHODS: Complete neurological evaluation and sequencing of the Notch 3 gene were carried out at King Faisal Specialist Hospital & Research Centre in 2007 on 2 families from Riyadh, Kingdom of Saudi Arabia and Sudan affected by CADASIL. RESULTS: The index cases had adult onset stroke, vascular dementia, behavioral and psychiatric symptoms and accelerated deaths. In both families, abnormal magnetic resonance imaging findings were detected in symptomatic and asymptomatic individuals. All Notch 3 exons were screened for mutations in both families and no known or novel mutation could be found; although, in one family the brain biopsy showed the typical granular osmiophilic material deposition and the vascular smooth muscle cells. CONCLUSION: This is the first 2 cases of CADASIL in Arabs, which occur without an obvious Notch 3 mutation.

Exome Sequencing: Mutilating Sensory Neuropathy with Spastic Paraplegia due to a Mutation in FAM134B Gene.

Hereditary sensory and autonomic neuropathies (HSANs) are a clinically and genetically heterogeneous group of disorders involving various sensory and autonomic dysfunctions. The most common symptoms of HSANs include loss of sensations of pain and temperature that frequently lead to chronic ulcerations in the feet and hands of the patient. In this case study, we present the clinical features and genetic characteristics of two affected individuals from two unrelated Saudi families presenting mutilating sensory loss and spastic paraplegia. We employed homozygosity mapping and exome sequencing which is an efficient strategy to characterize the recessive genes, thus obtaining a rapid molecular diagnosis for genetically heterogeneous disorders like HSAN. Subsequently, a nonsense mutation (c.926 C>G; p.S309⁎) in FAM134B was identified. In addition, we confirmed that the mutant FAM134B transcripts were reduced in these patients presumably disrupting the receptors of the degradative endoplasmic reticulum pathways that facilitate the autophagy processes.

LGMD1D myopathy with cytoplasmic and nuclear inclusions in a Saudi family due to DNAJB6 mutation.

Autosomal dominant LGMD1D has been described in multiple families in Asia, Europe, and USA. However, to the best of our knowledge, no cases of LGMD1D have been reported among native Bedouin Saudi families. Fifty Saudi families with LGMD were analyzed and the causative underlying genes were studied utilizing genome wide linkage, homozygosity mapping, and neurological gene panel. We identified one family of a Bedouin origin with LGMD1D. Two patients had progressive proximal and distal weakness, dysphagia, and respiratory symptoms. Creatinine kinase was normal. Muscle biopsy showed marked variation in myofibers size with scattered angular atrophic fiber, necrotic fibers, and myophagocytosis, with red-rimmed vacuoles depicting a sarcoplasmic body. Heterozygous c.C287T (p.P96L) variant in exon 5 of DNAJB6 (NM_005494) gene was found. This change is localized within glycine and phenylalanine rich domain and alter an amino acid residue. Our findings will expand on the existing genotypic and phenotypic spectrum of this disorder and aid in elucidating hidden mechanisms implicated in LGMD1D.

Riboflavin Has Neuroprotective Potential: Focus on Parkinson's Disease and Migraine.

With the huge negative impact of neurological disorders on patient's life and society resources, the discovery of neuroprotective agents is critical and cost-effective. Neuroprotective agents can prevent and/or modify the course of neurological disorders. Despite being underestimated, riboflavin offers neuroprotective mechanisms. Significant pathogenesis-related mechanisms are shared by, but not restricted to, Parkinson's disease (PD) and migraine headache. Those pathogenesis-related mechanisms can be tackled through riboflavin proposed neuroprotective mechanisms. In fact, it has been found that riboflavin ameliorates oxidative stress, mitochondrial dysfunction, neuroinflammation, and glutamate excitotoxicity; all of which take part in the pathogenesis of PD, migraine headache, and other neurological disorders. In addition, riboflavin-dependent enzymes have essential roles in pyridoxine activation, tryptophan-kynurenine pathway, and homocysteine metabolism. Indeed, pyridoxal phosphate, the active form of pyridoxine, has been found to have independent neuroprotective potential. Also, the produced kynurenines influence glutamate receptors and its consequent excitotoxicity. In addition, methylenetetrahydrofolate reductase requires riboflavin to ensure normal folate cycle influencing the methylation cycle and consequently homocysteine levels which have its own negative neurovascular consequences if accumulated. In conclusion, riboflavin is a potential neuroprotective agent affecting a wide range of neurological disorders exemplified by PD, a disorder of neurodegeneration, and migraine headache, a disorder of pain. In this article, we will emphasize the role of riboflavin in neuroprotection elaborating on its proposed neuroprotective mechanisms in opposite to the pathogenesis-related mechanisms involved in two common neurological disorders, PD and migraine headache, as well as, we encourage the clinical evaluation of riboflavin in PD and migraine headache patients in the future.

Clinical heterogeneity of PLA2G6-related Parkinsonism: analysis of two Saudi families.

BACKGROUND: Recessive mutations in PLA2G6 have been associated with different neurodegenerative disorders, including infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation and more recently, early-onset dystonia parkinsonism. METHOD: Targeted-next generation sequencing using a custom Neurology panel, containing 758 OMIM-listed genes implicated in neurological disorders, was carried out in two index cases from two different Saudi families displaying early-onset levodopa-responsive Parkinsonism with pyramidal signs and additional clinical features. The detected mutations were verified in the index cases and available family members by direct sequencing. RESULTS AND CONCLUSION: We identified a previously described PLA2G6 homozygous p.R741Q mutation in three affected and two asymptomatic individuals from two Saudi families. Our finding reinforces the notion of the broadness of the clinical spectrum of PLA2G6-related neurodegeneration.

Functional clinical outcomes in multiple sclerosis: Current status and future prospects.

For decades, the Expanded Disability Status Scale (EDSS) has been the principal measure of disability in clinical trials in patients with multiple sclerosis (MS) and in clinical practice. However, this test is dominated by effects on ambulation. Composite endpoints may provide a more sensitive measure of MS-related disability through the measurement of additional neurological functions. The MS Functional Composite (MSFC) includes a walking test (25-ft walk) plus tests of upper extremity dexterity (9-hole peg test) and cognitive function (Paced Auditory serial Addition test [PASAT]). Replacing PASAT with the Symbol Digit Modality test, a more sensitive test preferred by patients, may improve the clinical utility of the MSFC. In addition, disease-specific measures of QoL may be used alongside the MSFC (which does not include measurement of QoL). Clinical data suggest that disease-modifying therapies may delay or prevent relapse, and better composite measures will be valuable in the assessment of disease activity-free status in people with MS.

Parkinson's Disease in Saudi Patients: A Genetic Study.

Parkinson's disease (PD) is one of the major causes of parkinsonism syndrome. Its characteristic motor symptoms are attributable to dopaminergic neurons loss in the midbrain. Genetic advances have highlighted underlying molecular mechanisms and provided clues to potential therapies. However, most of the studies focusing on the genetic component of PD have been performed on American, European and Asian populations, whereas Arab populations (excluding North African Arabs), particularly Saudis remain to be explored. Here we investigated the genetic causes of PD in Saudis by recruiting 98 PD-cases (sporadic and familial) and screening them for potential pathogenic mutations in PD-established genes; SNCA, PARKIN, PINK1, PARK7/DJ1, LRRK2 and other PD-associated genes using direct sequencing. To our surprise, the screening revealed only three pathogenic point mutations; two in PINK1 and one in PARKIN. In addition to mutational analysis, CNV and cDNA analysis was performed on a subset of patients. Exon/intron dosage alterations in PARKIN were detected and confirmed in 2 cases. Our study suggests that mutations in the ORF of the screened genes are not a common cause of PD in Saudi population; however, these findings by no means exclude the possibility that other genetic events such as gene expression/dosage alteration may be more common nor does it eliminate the possibility of the involvement of novel genes.

Polyradiculopathy. A rare complication of neurobrucellosis.

Neurobrucellosis is chronic brucellosis affecting the nervous system. It may mimic many neurological diseases but it rarely presents as polyradiculopathy. Brucellar radiculopathy was diagnosed in 6 patients who presented with weakness of the lower extremities. Five patients had lumbar puncture, 4 had magnetic resonance imaging of lumbar spine and 4 had nerve conduction studies. Five patients had areflexia and weakness; one had areflexia with proprioceptive ataxia. All patients had positive Brucella serology; cerebrospinal fluid showed lymphocytic pleocytosis, elevated protein, normal-low glucose; brucella serology was positive in all specimens. Nerve conduction studies showed absent F-wave in 2 patients and polyradiculopathy with secondary motor axonopathy in 2 patients; motor conduction velocity was normal in all. Magnetic resonance imaging with gadolinium injection showed enhancement of lumbar nerve root in 3 patients, and no enhancement in one. All patients improved after treatment with antibiotics and lumbar root enhancement disappeared. Symptoms of myelopathy were unmasked after radiculopathy had resolved in one patient. In endemic areas, brucella infection should be considered in the differential diagnosis of radiculopathy. Radiculopathy is probably due to inflammation of the meninges and the intrathecal portion of the roots. The pathogenesis of myelopathy may involve demyelination as spasticity persists or worsens after radiculopathy improves.

Future of management of multiple sclerosis in the middle East: a consensus view from specialists in ten countries.

The prevalence of multiple sclerosis (MS) is now considered to be medium-to-high in the Middle East and is rising, particularly among women. While the characteristics of the disease and the response of patients to disease-modifying therapies are generally comparable between the Middle East and other areas, significant barriers to achieving optimal care for MS exist in these developing nations. A group of physicians involved in the management of MS in ten Middle Eastern countries met to consider the future of MS care in the region, using a structured process to reach a consensus. Six key priorities were identified: early diagnosis and management of MS, the provision of multidisciplinary MS centres, patient engagement and better communication with stakeholders, regulatory body education and reimbursement, a commitment to research, and more therapy options with better benefit-to-risk ratios. The experts distilled these priorities into a single vision statement: "Optimization of patient-centred multidisciplinary strategies to improve the quality of life of people with MS." These core principles will contribute to the development of a broader consensus on the future of care for MS in the Middle East.

Primary Sjogren's syndrome with central nervous system involvement.

OBJECTIVE: To describe the clinical, laboratory, and radiological features of Primary Sjogren's syndrome (PSS) with central nervous system (CNS) involvement. METHODS: A retrospective case series of 12 female patients with PSS and CNS involvement at King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia from 1991-2009. The diagnosis of PSS is defined by the American-European Diagnostic Criteria. We analyzed the clinical, radiological, and immunological features. RESULTS: The mean age was 40 years (range 16-58 years); all patient were females and presented with active neurological symptoms. The neurological involvement preceded the classic sicca symptoms (33%). Eight patients (66%) presented with myelopathy, 9 patients (75%) had optic neuritis, and the rest had variable neurological signs. Immunological tests (anti-Sjogren's syndrome A and anti-Sjogren's syndrome B) were high in 7 patients (58%). Minor salivary gland biopsy revealed inflammatory cell infiltrate in 11 patients (92%). Brain MRI showed scattered white matter changes in 7 patients (58%). Spine MRI showed multiple foci of hyperintensity in T2-weighted image in 6 patients (50%), and long segment of hyperintensity at the cervical spinal cord in 2 patients (16%). CONCLUSION: Our findings demonstrate that CNS involvements in PSS have great clinical variability and could precede the classic sicca symptoms by years. Primary Sjogren's syndrome can mimic multiple sclerosis (primary progressive multiple sclerosis or relapsing remitting multiple sclerosis), therefore a screening test for PSS should be considered in suspected cases. A well-defined management protocol awaits studies with larger case numbers.