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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]
  • Facial numbness and weakness are also common.[medical-dictionary.thefreedictionary.com]
  • 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]
  • The genetic variants identified thus far make only weak individual contributions to MS susceptibility.[ncbi.nlm.nih.gov]
  • When relapse or worsening of symptoms occur, physical and occupational therapy can help minimize muscle weakness and help restore movement.[multiplesclerosisnewstoday.com]
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]
  • 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]
  • Fatigue is also common with this and all other forms of multiple sclerosis.[verywell.com]
Falling
  • Somewhere between 2 percent to 5 percent of all MS cases fall into the pediatric category, affecting anywhere from 8,000 to 20,000 children. Several thousand more children and teens may have symptoms of MS, but no firm diagnosis.[sharecare.com]
  • 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]
  • Between the optic neuritis, numbness, fatigue, dropping things, tripping and falling... READ MORE Of late, the MS has been giving me a pretty good a** whuppin’.[multiplesclerosis.net]
  • 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]
Difficulty Walking
  • 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]
  • 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]
  • 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]
  • Initial symptoms often include: Muscle weakness, causing difficulty walking Loss of coordination or balance Numbness, "pins and needles," or other abnormal sensations Visual disturbances, including blurred or double vision.[medical-dictionary.thefreedictionary.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]
  • vision , [19] very pronounced reflexes , muscle spasms , or difficulty in moving; difficulties with coordination and balance ( ataxia ); problems with speech or swallowing , visual problems ( nystagmus , optic neuritis or double vision ), feeling tired[en.wikipedia.org]
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]
Facial Numbness
Emotional Lability
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]
  • Symptoms are seen in only around one percent of people with PPMS but may include: Problems with swallowing ( dysphagia ) Dizziness, vomiting, or nausea Rapid, involuntary movements of the eyes ( nystagmus ) Vision impairment or loss Impaired cognitive[verywell.com]
  • […] 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]
Ataxia
  • Spastic paraparesis and progressive ataxia are principal symptoms in this subset of patients.[symptoma.com]
  • HDLS (Hereditary Diffuse Leukodystrophy with Spheroids) is a hereditary leukodystrophy whose main clinical manifestations include parkinsonism, spasticity, and ataxia.[ncbi.nlm.nih.gov]
  • […] rhythmic jerkiness A weakness or immobility on one side of the body, known as spastic hemiparesis , which may affect the legs, arms, or hands Exercise intolerance (the decreased ability to perform exercise) Clumsiness and lack of muscle coordination ( ataxia[verywell.com]
  • Later in the course of the disease there may be extreme emotional lability, ataxia, abnormal reflexes, and difficulty in urinating.[medical-dictionary.thefreedictionary.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]
Tremor
  • Symptoms in-clude pain, weakness, numbness, tingling, paralysis, tremors, and muscle dysfunction.[medical-dictionary.thefreedictionary.com]
  • Known as progressive cerebellar syndrome (PCS), the disorder affects one of every 10 persons diagnosed with PPMS and can often manifest with: Impairment of fine hand movement due to severe intention tremor Loss of muscle tone (hypotonia) Loss of balance[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]
  • He published what now is known as the "Charcot Triad", consisting in nystagmus , intention tremor , and telegraphic speech (scanning speech) [118] Charcot also observed cognition changes, describing his patients as having a "marked enfeeblement of the[en.wikipedia.org]
Vertigo
  • Other early signs are muscle weakness, vertigo, and visual disturbances, such as nystagmus, diplopia (double vision), and partial blindness.[medical-dictionary.thefreedictionary.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]
  • 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]
  • 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]
Nystagmus
  • Double vision or eye tremor ( nystagmus ) may result from involvement of the nerve pathways controlling movement of the eye muscles.[medical-dictionary.thefreedictionary.com]
  • Symptoms are seen in only around one percent of people with PPMS but may include: Problems with swallowing ( dysphagia ) Dizziness, vomiting, or nausea Rapid, involuntary movements of the eyes ( nystagmus ) Vision impairment or loss Impaired cognitive[verywell.com]
  • […] 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), visual problems (nystagmus[disabled-world.com]
  • He published what now is known as the "Charcot Triad", consisting in nystagmus , intention tremor , and telegraphic speech (scanning speech) [118] Charcot also observed cognition changes, describing his patients as having a "marked enfeeblement of the[en.wikipedia.org]
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]
  • Later symptoms may include: Fatigue Muscle spasticity and stiffness Tremors Paralysis Pain Vertigo Speech or swallowing difficulty Loss of bowel and bladder control Incontinence, constipation Sexual dysfunction Cognitive changes.[medical-dictionary.thefreedictionary.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]
  • incontinence, pain, paralysis, tremor, nystagmus, speech disturbance (depending on central nervous system sites affected) multiple sclerosis (m lˑ·ti·pul skl ·rōˑ·s s) , n a disorder of the central nervous system caused by damage of the myelin sheath[medical-dictionary.thefreedictionary.com]
Urinary Retention
  • Therapeutic measures include medications to diminish muscle spasticity; measures to overcome urinary retention (such as credé's method or intermittent catheterization ); speech therapy; and physical therapy to maintain muscle tone and avoid orthopedic[medical-dictionary.thefreedictionary.com]

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

  • 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 magnetic[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]
  • 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]
  • Data regarding MS symptoms, treatment, gait, and function were abstracted from the PT clinic notes.[ncbi.nlm.nih.gov]

Prognosis

  • 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]
  • Prognosis Worse if male, age 40 at presentation, rapidly progressive, with motor dysfunction (i.e., with cerebellar or corticospinal activity).[medical-dictionary.thefreedictionary.com]

Etiology

  • Many neurodegenerative disorders share a common pathophysiological pathway involving axonal degeneration despite different etiological triggers.[ncbi.nlm.nih.gov]
  • This progressive etiology would provide valuable insight into PPMS development and may also shed light on SPMS progression.[clinicaltrials.gov]
  • ., 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]
  • Normal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency. Neurology (2010) 75(18):1617–22. doi:10.1212/WNL.0b013e3181fb449e PubMed Abstract CrossRef Full Text Google Scholar 62. Stadelmann C, Wegner C, Bruck W.[journal.frontiersin.org]

Epidemiology

  • The objective of this study was to perform an updated systematic review of the epidemiology of PPMS in LATAM. 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]
  • 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 10 Emerging drugs for primary progressive multiple sclerosis. ( 29638150 ) Narayan R.N....StA1ve O. 2018 11 A systematic review about the epidemiology[malacards.org]
  • Epidemiology Onset in younger, often female adults, affecting 1:2500 (US), commonly associated with HLA-A3, B7 and Dw2 haplotypes. MS is increased in a south-to-north gradient in the Northern hemisphere (i.e., more common in colder climates).[medical-dictionary.thefreedictionary.com]
Sex distribution
Age distribution

Pathophysiology

  • Many neurodegenerative disorders share a common pathophysiological pathway involving axonal degeneration despite different etiological triggers.[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.[ncbi.nlm.nih.gov]
  • 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 process affecting both the brain with CLs and the retina[ncbi.nlm.nih.gov]
  • The pathophysiology of primary progressive (PP) multiple sclerosis (MS) involves diffuse axonal degeneration which is believed to start early in the disease process, even before the onset of clinical symptoms.[ncbi.nlm.nih.gov]
  • Figure 3: B cells in the pathophysiology of MS [8-11].[omicsonline.org]

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