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Primary Progressive Multiple Sclerosis

Primary progressive multiple sclerosis (PPMS) is one of the subtypes of multiple sclerosis (MS) distinguished by a slow and irreversible course of myelopathy and overall neurological decline. Contrary to other MS forms, significant female predilection is not observed. Spastic paraparesis and progressive ataxia are principal symptoms in this subset of patients. The diagnosis is made by clinical criteria, findings obtained from magnetic resonance imaging (MRI) of the brain and/or spinal cord, as well as cerebrospinal fluid (CSF) reports.


Presentation

Primary progressive multiple sclerosis is a well-recognized form of multiple sclerosis that is characterized by progressive damage to the central nervous system (CNS) and subsequent decline in overall functioning and quality of life [1] [2] [3] [4]. The exact pathogenic mechanism by which neuronal degeneration occurs, however, remains unclear [1] [4]. It is recognized in about 10-15% of all cases suffering from MS and is one of the rare entity that equally affects both genders [1] [5] [4] [6] [7]. In fact, some studies propose that males are more frequently affected than females and that MS patients are more likely to develop PPMS at an older age [1] [2] [7]. Compared to relapsing-remitting multiple sclerosis (RRMS), which encompasses the vast majority of MS patients and presents with optic neuritis and other isolated spinal cord/brainstem abnormalities [2], the clinical presentation of PPMS is comprised of two main symptoms - spastic paraplegia (often described with an unclear sensory level) and ataxia [2] [5]. These signs appear due to progressive atrophy of the spinal cord and the cerebellum, whereas the appearance of brainstem abnormalities, visual deficits, sexual dysfunction, cognitive decline, and inability to maintain sphincter control, are less commonly reported in PPMS [1] [2] [7]. Primary progressive multiple sclerosis has a poor prognosis than other types of MS, mainly because of a delayed diagnosis and an aggressive neurological deterioration [5] [7].

Weakness
  • Her symptoms started at the age of 29 years with insidious onset of pyramidal weakness in the left leg. The cerebrospinal fluid examination showed four intrathecal immunoglobulin G bands.[ncbi.nlm.nih.gov]
  • The genetic variants identified thus far make only weak individual contributions to MS susceptibility.[ncbi.nlm.nih.gov]
  • If you have primary progressive multiple sclerosis (PPMS), you probably first saw a doctor because your legs were weak or you had trouble walking. Those are the most common symptoms of this type of MS. Once it starts, PPMS gets worse over time.[webmd.com]
  • When relapse or worsening of symptoms occur, physical and occupational therapy can help minimize muscle weakness and help restore movement.[multiplesclerosisnewstoday.com]
  • […] such as double vision Spasticity or stiffness of the muscles Difficulty controlling the bladder or bowels Problems with cognition, such as learning and memory or information processing Difficulty with walking and coordination Trouble walking Muscle weakness[cedars-sinai.edu]
Fatigue
  • “We also have additional data that shows we have an effect on fatigue (a very important aspect of MS, 75% of patients have fatigue).[mdmag.com]
  • Symptoms of the latter may include itchy skin, rash, hives, skin redness, flushing, low blood pressure, fever, fatigue, dizziness, headache, throat irritation, and shortness of breath.[clinicaladvisor.com]
  • Fatigue is also common with this and all other forms of multiple sclerosis.[verywell.com]
  • You’ll take medications to help you with: Tight muscles Bladder and bowel problems Pain Fatigue You’ll also get rehabilitation, such as physical, occupational, or speech therapy.[webmd.com]
  • This may be experienced through increased: Fatigue Numbness or tingling Vision problems, such as double vision Spasticity or stiffness of the muscles Difficulty controlling the bladder or bowels Problems with cognition, such as learning and memory or[cedars-sinai.edu]
Difficulty Walking
  • A key symptom associated with PPMS is difficulty walking. This may result from the damage to the spinal cord that occurs with PPMS. MRI scans may be used to track the progression of MS.[medicalnewstoday.com]
  • People with PPMS may have trouble with balance and coordination or have difficulty walking.[healthline.com]
  • For instance, MS patients may have difficulty walking, experience poor vision, or encounter bowel problems. The excitement surrounding Ocrelizumab is that it’s the first drug to show benefit for primary progressive multiple sclerosis.[sitn.hms.harvard.edu]
  • Unlike relapsing forms of MS, primary progressive MS patients develop chronic symptoms of MS – often gradual weakness and difficulty walking – without experiencing a relapse or attack.[medicalxpress.com]
  • Affected individuals may have tremors, muscle stiffness (spasticity), exaggerated reflexes (hyperreflexia), weakness or partial paralysis of the muscles of the limbs, difficulty walking, or poor bladder control.[icdlist.com]
Falling
  • If this happens I informed this patient he may fall outside of the licensed indication, for example his PPMS may not be active enough. In addition, if and when the EMA licenses ocrelizumab for PPMS then NICE has to green-light it for use in the NHS.[multiple-sclerosis-research.blogspot.com]
  • First, 85 percent of individuals diagnosed with MS begin with the RRMS form, and after many years, RRMS usually advances to SPMS – so clearly the vast majority of patients fall under these categories.[mymsaa.org]
  • In the clinical trial data released last fall, which covered 732 people with primary progressive MS, people who took the drug had a 24 percent reduction in the progression of disability after 12 weeks compared to those who received a placebo.[statnews.com]
Blurred Vision
  • The damage stops messages from being passed along the nerves, leading to symptoms including tiredness and blurred vision. Ocrelizumab works by killing the cell which attacks the myelin sheath.[telegraph.co.uk]
  • Problems with vision This can include double vision, blurred vision, inability to identify colors and contrasts, and pain when moving your eyes.[healthline.com]
Muscular Atrophy
  • In late-stage Roche, they have treatments that are being tested for Alzheimer’s disease, Autism, and for Spinal Muscular Atrophy.[mdmag.com]
  • Roche has more than a dozen investigational medicines in clinical development for diseases that include multiple sclerosis, Alzheimer’s disease, spinal muscular atrophy, Parkinson’s disease and autism.[finance.yahoo.com]
  • 脊髄性筋萎縮症 Spinal muscular atrophy, SMA Type I 脊髄性筋萎縮症(SMA Type I) 1 HPS0158 HPS0159 Spinal muscular atrophy, SMA Type II 脊髄性筋萎縮症(SMA Type II) 1 不要 有 HPS1391 HPS1392 HPS1393 HPS1394 HPS1395 HPS1396 Spinal muscular atrophy 脊髄性筋萎縮症 1 不要 HPS0932 HPS0933 HPS0934[cell.brc.riken.jp]
Dizziness
  • Symptoms of the latter may include itchy skin, rash, hives, skin redness, flushing, low blood pressure, fever, fatigue, dizziness, headache, throat irritation, and shortness of breath.[clinicaladvisor.com]
  • […] vision Spasticity or stiffness of the muscles Difficulty controlling the bladder or bowels Problems with cognition, such as learning and memory or information processing Difficulty with walking and coordination Trouble walking Muscle weakness Paralysis Dizziness[cedars-sinai.edu]
  • […] and feet, back pain, and muscle spasms) Electric-shock sensations that run down the back and limbs when the neck is bent (Lhermitte sign) Trouble walking Vision problems Muscle weakness Trouble staying balanced Paralysis Numbness Prickling feelings Dizziness[hopkinsmedicine.org]
  • Symptoms include numbness, weakness, and dizziness. People with PPMS may have trouble with balance and coordination or have difficulty walking.[healthline.com]
  • Dizziness Those with PPMS may have episodes of dizziness and lightheadedness. Others may experience vertigo, a sensation that they’re spinning and losing their balance.[healthline.com]
Ataxia
  • Spastic paraparesis and progressive ataxia are principal symptoms in this subset of patients.[symptoma.com]
  • Abstract HDLS (Hereditary Diffuse Leukodystrophy with Spheroids) is a hereditary leukodystrophy whose main clinical manifestations include parkinsonism, spasticity, and ataxia.[ncbi.nlm.nih.gov]
  • This condition, known as progressive cerebellar syndrome (PCS), is seen less often than progressive myelopathy but can manifest with: Tremor: Impairment of fine hand movement due to severe intention tremor Hypotonia: Loss of muscle tone Gait ataxia: Loss[verywell.com]
  • ICD-10-CM G35 is grouped within Diagnostic Related Group(s) (MS-DRG v 36.0): 058 Multiple sclerosis and cerebellar ataxia with mcc 059 Multiple sclerosis and cerebellar ataxia with cc 060 Multiple sclerosis and cerebellar ataxia without cc/mcc Convert[icd10data.com]
  • Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia, and bladder dysfunction.[icdlist.com]
Dysarthria
  • A 28-year-old woman developed progressive spastic gait and dysarthria. Brain T2/FLAIR-weighted magnetic resonance imaging showed bilateral high signal intensity lesions in the parietal deep white matter, which subsequently extended anteriorly.[ncbi.nlm.nih.gov]
  • Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia, and bladder dysfunction.[icdlist.com]
  • MS can cause a variety of symptoms, including changes in sensation (hypoesthesia), muscle weakness, abnormal muscle spasms, or difficulty in moving; difficulties with coordination and balance (ataxia); problems in speech (dysarthria) or swallowing (dysphagia[disabled-world.com]
Vertigo
  • Common symptoms of an MS relapse or attack include new numbness, tingling, or weakness in an area of the body, painful loss of vision, vertigo, double vision, and sometimes other less common symptoms.[medicalxpress.com]
  • Others may experience vertigo, a sensation that they’re spinning and losing their balance. Bladder and bowel problems Bladder and bowel problems can range from incontinence, to the constant need to go, to constipation.[healthline.com]
  • Examples of common clinical features include 23,24 : brainstem and cranial nerve involvement: optic neuritis internuclear ophthalmoplegia (often bilateral) trigeminal neuralgia diplopia (e.g. due to abducens nerve palsy ) vertigo cerebellum involvement[radiopaedia.org]
Tremor
  • This condition, known as progressive cerebellar syndrome (PCS), is seen less often than progressive myelopathy but can manifest with: Tremor: Impairment of fine hand movement due to severe intention tremor Hypotonia: Loss of muscle tone Gait ataxia: Loss[verywell.com]
  • Affected individuals may have tremors, muscle stiffness (spasticity), exaggerated reflexes (hyperreflexia), weakness or partial paralysis of the muscles of the limbs, difficulty walking, or poor bladder control.[icdlist.com]
Sexual Dysfunction
  • These signs appear due to progressive atrophy of the spinal cord and the cerebellum, whereas the appearance of brainstem abnormalities, visual deficits, sexual dysfunction, cognitive decline, and inability to maintain sphincter control, are less commonly[symptoma.com]
  • dysfunction Causes and Risk Factors Ten percent of all multiple sclerosis patients are diagnosed with PPMS.[cedars-sinai.edu]
  • Other symptoms include: visual disturbances bladder dysfunction sexual dysfunction cognitive changes or mood disorders, including depression Diagnosing any form of MS can take a long time. That’s because no single test can confirm MS.[healthline.com]
  • Additional symptoms that a person with PPMS may experience include: changes in mood depression muscle weakness numbness paralysis problems thinking clearly problems with bowel and bladder control sexual dysfunction tingling trouble maintaining balance[medicalnewstoday.com]
  • Beyond Ocrevus, your doctor can give you prescription medications to help you manage your MS symptoms, such as: MS-related fatigue Pain Gait impairment Bladder and/or bowel dysfunction Depression Cognitive impairment Sexual dysfunction Muscle spasms Rehabilitation[verywell.com]
Urinary Incontinence
  • incontinence others: fatigue depression Uhthoff phenomenon: heat and exercise worsen symptoms cognitive decline Classification A number of patterns of longitudinal disease have been described 11,12 : relapsing-remitting most common (70% of cases) patients[radiopaedia.org]

Workup

Because the various clinical forms of MS might be indistinguishable in their initial stages [2], particularly the different types of progressive MS, the physician, with his/her ability to obtain a detailed patient history and conduct a thorough physical examination, plays a crucial role in recognizing MS early on. Firstly, key information regarding the presence of symptoms, their duration, as well as progression, should be obtained, followed by a meticulous neurological evaluation. In recent years, diagnostic criteria for identifying PPMS have been designed and consist of the following [2] [4] [5] [7]:

  • Progression of the disease for at least a period of 1 year.
  • MRI findings - Either 9 lesions on T2-weighted studies or ≥ 4 lesions on T1-weighted studies in the brain, each exhibiting positive visual evoked potentials (VEP), or at least 2 focal spinal cord lesions seen on T2-weighted studies. Two out of three of the mentioned findings are required for the diagnosis of PPMS [3].
  • The presence of oligoclonal bands or abnormally high levels of immunoglobulin (Ig) G antibodies in the CSF.

Treatment

  • OBJECTIVES: To investigate, during the 5-year period without treatment after termination of a 2-year clinical trial of interferon beta-1b for the treatment of primary progressive multiple sclerosis, differences in the evolution of clinical variables and[ncbi.nlm.nih.gov]
  • Patients with primary progressive multiple sclerosis underwent serial magnetic resonance imaging scans before (pretreatment phase) and during (treatment phase) amiloride treatment for a period of 3 years.[ncbi.nlm.nih.gov]
  • KEYWORDS: Multiple sclerosis; disease-modifying therapy; immunomodulatory drugs; immunosuppressive drugs; ocrelizumab; primary progressive; treatment[ncbi.nlm.nih.gov]
  • (RR 0.89, 95% CI 0.55 to1.43), and it was associated with a greater frequency of treatment-related adverse events (RR 1.90, 95% CI 1.45-2.48).[ncbi.nlm.nih.gov]
  • Co-treatment with interferon-beta in relapsing-remitting multiple sclerosis was irrelevant to vitamin D levels. After six months nutritional treatment, no significant changes in neurological signs were observed in any group.[ncbi.nlm.nih.gov]

Prognosis

  • BACKGROUND: Primary progressive multiple sclerosis (PPMS) carries the worst prognosis of the multiple sclerosis (MS) subtypes and is currently untreatable.[ncbi.nlm.nih.gov]
  • Primary progressive multiple sclerosis has a poor prognosis than other types of MS, mainly because of a delayed diagnosis and an aggressive neurological deterioration.[symptoma.com]
  • Approximately 10 to 15% of patients present with PPMS, which is characterized by continuous disease progression from the onset of disease, i.e. without relapses and remissions, for which prognosis is considered as poor due to the relatively rapid development[globenewswire.com]
  • Prognosis is variable and depends on the pattern of disease a patient has (e.g. primary progressive carries a worse prognosis than relapsing-remitting).[radiopaedia.org]
  • Being able to characterize the course of your disease course at different points in time helps you and your MS care provider have important conversations about your treatment options and prognosis.[nationalmssociety.org]

Etiology

  • This progressive etiology would provide valuable insight into PPMS development and may also shed light on SPMS progression.[clinicaltrials.gov]
  • Abstract Many neurodegenerative disorders share a common pathophysiological pathway involving axonal degeneration despite different etiological triggers.[ncbi.nlm.nih.gov]
  • 結節性硬化症 Tuberous sclerosis complex (TSC), unknown genetic etiology 結節性硬化症、遺伝子型不明 1 不要 有 HPS2395 HPS2396 HPS2397 HPS2398 HPS2399 HPS2400 159.[cell.brc.riken.jp]
  • ., Principles of Neurology, 6th ed, p903) Chronic disease characterized by presence of numerous areas of demyelination in the central nervous system with symptoms such as weakness, incoordination, paresthesis, and speech disturbances; the etiology is[icd10data.com]
  • […] various investigations (see McDonald diagnostic criteria for multiple sclerosis ), including 19 : typical history oligoclonal bands in CSF immunoglobulin G in serum abnormal visual evoked potential MR imaging lack of viable alternative diagnosis The exact etiology[radiopaedia.org]

Epidemiology

  • The objective of this study was to perform an updated systematic review of the epidemiology of PPMS in LATAM. METHODS: We conducted a systematic review of published epidemiological articles of PPMS from January 1997 to June 2017.[ncbi.nlm.nih.gov]
  • In this review, we summarize the knowledge regarding the clinical, epidemiological, imaging, and pathological characteristics of PPMS and compare those characteristics with RRMS and SPMS.[ncbi.nlm.nih.gov]
  • Abstract Epidemiological data on primary progressive multiple sclerosis (PPMS) are scarce. This study was aimed to evaluate the burden of PPMS in Italy with healthcare resources utilisation and costs for Italian National Health System (INHS).[ncbi.nlm.nih.gov]
  • […] progressive multiple sclerosis: insights from the INFORMS study. ( 29560379 ) Miller D.H....Wolinsky J.S. 2018 14 Emerging drugs for primary progressive multiple sclerosis. ( 29638150 ) Narayan R.N....StA1ve O. 2018 15 A systematic review about the epidemiology[malacards.org]
Sex distribution
Age distribution

Pathophysiology

  • […] thalamus and visual cortex volume (respectively, p   0.01 and p CONCLUSION: Our results suggest that RNFL thinning and GCIPL thinning/MV decrease may be explained by alternative mechanisms including retrograde trans-synaptic degeneration and/or a common pathophysiologic[ncbi.nlm.nih.gov]
  • Subcortical GM volume, particularly of the thalamus, is a strong predictor of cognitive performance, suggesting it has a central role in the pathophysiology of PPMS-related cognitive dysfunction. 2016 John Wiley & Sons A/S.[ncbi.nlm.nih.gov]
  • Author information 1 Faculty of Medicine, Division of Neurology, University of British Columbia, Vancouver, Canada. m.w.koch@neuro.umcg.nl Abstract The pathophysiology of primary progressive (PP) multiple sclerosis (MS) involves diffuse axonal degeneration[ncbi.nlm.nih.gov]
  • Abstract Many neurodegenerative disorders share a common pathophysiological pathway involving axonal degeneration despite different etiological triggers.[ncbi.nlm.nih.gov]
  • View Article Google Scholar Schmidt S: S100B: pathogenetic and pathophysiologic significance in neurology. Nervenarzt. 1998, 69: 639-646. 10.1007/s001150050323.[jnrbm.biomedcentral.com]

Prevention

  • Unfortunately, the lack of any warning symptoms hampers any future prevention trial in this population.[ncbi.nlm.nih.gov]
  • Expert commentary: The recent encouraging results of the ocrelizumab trial in PP MS, the first to reach the primary disability endpoint, indicate B cells as a promising therapeutic target to prevent disease progression.[ncbi.nlm.nih.gov]
  • Vitamin D directly and indirectly regulates the differentiation, activation of CD4 T-lymphocytes and can prevent the development of autoimmune processes, and so it may be involved in neuroprotective elements in MScl.[ncbi.nlm.nih.gov]
  • The observed relationship between imaging measures and disability suggests that early spinal neurodegeneration may underlie clinical impairment, and should be targeted in future clinical trials with neuroprotective agents to prevent the development of[ncbi.nlm.nih.gov]

References

Article

  1. Miller DH, Leary SM. Primary-progressive multiple sclerosis. Lancet Neurol. 2007;6(10):903-912.
  2. Rice CM, Cottrell D, Wilkins A, Scolding NJ. Primary progressive multiple sclerosis: progress and challenges. J Neurol Neurosurg Psychiatry. 2013;84(10):1100-1106.
  3. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292-302.
  4. Ontaneda D, Fox RJ. Progressive multiple sclerosis. Curr Opin Neurol. 2015;28(3):237-243.
  5. Hurwitz BJ. The diagnosis of multiple sclerosis and the clinical subtypes. Ann Indian Acad Neurol. 2009;12(4):226-230.
  6. Ebers GC. Natural history of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2001;17:16–9. ii.
  7. Khan F, Amatya B, Turner-Stokes L. Symptomatic Therapy and Rehabilitation in Primary Progressive Multiple Sclerosis. Neurol Res Int. 2011;2011:740505.

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Last updated: 2018-06-21 17:16