Multiple sclerosis (MS) is a chronic degenerative disease of the CNS characterized by demyelination and axonal degeneration in the brain and spinal cord, which are caused by an immune-mediated inflammatory process. The prevalence of MS is higher among women and people in temperate regions such as Europe and North America. Impaired vision (due to retrobulbar neuritis) is usually the first manifestation of MS; other neurological deficits appear as the disease progresses. The most common clinical course is characterized by exacerbations followed by periods of complete or incomplete remission. Diagnosis is made using clinical and MRI findings to identify the dissemination of CNS lesions in time and space. Characteristic MRI findings are demyelinated sclerotic plaques primarily located in white matter. Differential diagnoses of MS include other chronic demyelinating diseases and neurological infections (e.g., borreliosis, neurosyphilis). Acute exacerbations of MS are usually treated with high-dose glucocorticoids. Between exacerbations, patients may be treated with disease-modifying drugs (e.g., interferon beta, glatiramer acetate, natalizumab). There is currently no definitive treatment for MS.
The etiology of multiple sclerosis is unclear; it is believed to develop in genetically predisposed people who have been exposed to certain environmental factors.
- Genetic predisposition
- Environmental risk factors 
- Remission: a period of recovery after an exacerbation during which clinical symptoms resolve completely or almost completely
- Pseudorelapse: recurrence or significant worsening of existing symptoms due to stressors (e.g., infection, heat)
- Radiologically isolated syndrome (RIS) 
- Clinically isolated syndrome (CIS)
- Diffuse cerebral sclerosis (Schilder disease) 
Clinical course 
|Clinical phenotypes of multiple sclerosis |
|Relapsing-remitting MS (RR-MS)|| || |
|Secondary progressive MS (SP-MS)|| || |
|Primary progressive MS (PP-MS)|| || |
- Pathophysiology of MS is characterized by autoimmune inflammation, demyelination, and axonal degeneration.
- Most commonly accepted theory: Activation of autoreactive T-lymphocytes; → inflammatory processes → focal demyelination with partial preservation of axons (acute plaques) → loss of axons and atrophy of oligodendrocytes (chronic plaques) → gliosis → inadequate remyelination
- B-lymphocyte dysfunction: The following suggests that B-lymphocytes play a role in the pathogenesis of MS, although the exact mechanism of their involvement is unclear.
- Progressive phenotypes (forms) of MS are characterized by 
- Constitutional symptoms: fatigue, headache
- Optic neuritis ; 
- (INO) as a result of a lesion in the medial longitudinal fasciculus (MLF)
Demyelination of spinal cord tracts
- Lhermitte sign: a shooting electric sensation that travels down the spine upon flexion of the neck
- Pyramidal tract lesion: upper motor neuron weakness, spasticity, hyperreflexia, positive Babinski sign, impaired gait
- Dorsal spinal column lesion: loss of vibration and fine-touch sensation, numbness, paresthesias, sensory ataxia usually involving the trunk or one or more limbs
- Neuropathic pain
- Absent abdominal reflex 
- Cerebellar involvement: poor postural control, imbalance, gait dysfunction, Charcot neurological triad: of scanning speech, nystagmus, and intention tremors
- Cranial nerve palsies: diplopia, trigeminal sensory neuralgia, facial palsy 
- Autonomic dysfunction: bowel and bladder neurogenic disorders (e.g., urinary incontinence), impaired sexual function
- Changes in mental state: depression, emotional changes, memory deficits, impaired concentration
- Uhthoff phenomenon: a reversible exacerbation of neurological symptoms following an increase in body temperature, e.g., physical exertion, a warm bath, or fever
Uhthoff phenomenon triggered by a viral infection may mimic an exacerbation of MS.
MS is a chronic condition that typically manifests in a relapsing-remitting form characterized by episodic CNS dysfunction (exacerbations) with at least partial recovery between episodes.
General principles 
- Diagnosis of MS depends on a combination of clinical findings (e.g., optic neuritis, Lhermitte sign, sensory abnormalities, cerebellar signs), imaging, and laboratory results.
- Consider early specialist (i.e., neurology) consultation for patients with history and clinical features suggestive of MS.
- The McDonald Criteria for both DIT and DIS must both be met to confirm a diagnosis of MS: 
- In some cases, electrophysiological, CSF, and laboratory studies may be necessary to support the diagnosis and exclude differential diagnoses. 
MRI is the imaging study of choice for the diagnosis and monitoring of MS.
Typical findings on MRI
- Multiple sclerotic plaques (most commonly found in the periventricular white matter) ; with finger-like radial extensions (Dawson fingers) related to demyelination and reactive gliosis 
- Contrast-enhancement of active lesions; usually resolves after 2–8 weeks 
Consider further testing for patients with nondiagnostic MRI and to rule out differential diagnoses.
CSF examination: commonly performed to support MS diagnosis and rule out other conditions 
- Oligoclonal bands 
- Other common findings: moderate lymphocytic pleocytosis, increased myelin basic protein 
Evoked potentials: Consider visual evoked potentials for patients with symptoms related to vision. 
- Can provide objective evidence of lesions
- May show evidence of increased latency, which occurs due to slowed optive nerve conduction.
- Laboratory studies: to rule out other diagnoses, based on clinical suspicion 
Autoimmune diseases associated with inflammatory demyelination
Neuromyelitis optica spectrum disorders (NMOSD; previously known as Devic disease or neuromyelitis optica) 
- Definition: immune-mediated, chronic inflammatory disorders of the CNS that primarily affect the optic nerve and spinal cord
- Incidence: 0.3-4.4 per 100,000
- More prevalent in individuals of African and Asian descent than in white populations
- Peak onset: 40-60 years
- Clinical features
Diagnosis: based on
- Serological evidence of anti-aquaporin-4 (AQP4)
- The presence of clinical characteristics
- Typical MRI findings (see clinical criteria for NMOSD with negative AQP4-IgG or unknown status below)
|Diagnostic criteria of NMOSD based on AQP4-IgG status|
|Serological criteria||Clinical criteria||Additional criteria|
|Positive AQP4-IgG|| |
|Negative AQP4-IgG or unknown status|| |
- First line: high-dose glucocorticoid therapy for 3–5 days followed by a taper for 2–8 weeks
- Plasmapheresis in severe, refractory cases
- The following biological agents are approved for use in patients with positive AQP4-IgG
- Immune modulators used off-label (azathioprine, rituximab) may also reduce the risk of acute attacks
- Natalizumab and IFN-β (effective MS treatment options) can trigger NMOSD exacerbations
(ADEM, acute demyelinating encephalomyelitis) 
- Definition: an immune-mediated, demyelinating CNS disease of parainfectious origin (e.g., measles) or after vaccinations (less common)
- Epidemiology: mostly affects children and young adults
- Clinical features: rapidly progressing, usually monophasic, course with multifocal symptoms
Transverse myelitis 
- Definition: an acute or subacute inflammatory myelopathy that results in motor, sensory, and autonomic symptoms below the level of the affected segment
- Rare condition (< 5 cases per million)
- Bimodal incidence: peak in the 2nd and 4th decade of life
- Most often idiopathic
- Parainfectious (e.g., enteroviruses, EBV, CMV, Listeria monocytogenes, B. burgdorferi)
- CNS demyelinating disorders (e.g., ,
- Systemic inflammatory autoimmune disorders (e.g., SLE, sarcoidosis)
- Paraneoplastic syndromes
- Drug-induced (e.g., TNF-α inhibitors, chemotherapeutic agents)
- Course of the disease
- Neurologic dysfunction
|Overview of transverse myelitis types|
|Types of TM||Manifestations||MRI findings|
|Longitudinally limited TM (LLTM)||Acute complete TM (ACTM)|
|Acute partial TM (APTM)1|| |
|Longitudinally extensive TM (LETM)|| |
- MRI of the brain and spine with and without gadolinium: investigation of choice
- Laboratory studies
- CSF analysis 
- Further investigations based on clinical presentation and suspected underlying cause, e.g., paraneoplastic profile to rule out paraneoplastic syndrome, CT chest to rule out sarcoidosis, nerve conduction studies to help rule out GBS and peripheral neuropathies
- Differential diagnoses
- Acute management
- First-line: immediate high-dose IV corticosteroids
- Supportive care: prevent decubitus ulcer and/or thrombosis, manage urinary retention, gastroparesis, constipation, and respiratory failure in patients with high cervical cord lesions
- Long-term management
- Acute management
- Vasculitis: resulting from connective tissue disorders (e.g., SLE, polyarteritis nodosa, granulomatosis with polyangiitis, Behcet disease)
The differential diagnoses listed here are not exhaustive.
General principles 
- All patients: Refer to a neurologist for specialized management.
- Acute exacerbations: Treat all acute exacerbations that affect physical functioning.
- Long-term management: Combine pharmacological and nonpharmacological measures to prevent exacerbations and improve quality of life.
Treatment should be initiated as early as possible; the goals of treatment are to manage the primary exacerbation, prevent further exacerbations, and slow disease progression.
Management of acute exacerbations 
If an acute exacerbation of MS is suspected, a specialist should be consulted immediately for management.
- Preferred therapy:
- Alternatives: plasmapheresis, ACTH gel 
- Perform a thorough neurological examination and compare with the patient's baseline.
- Evaluate for possible infectious triggers. 
- Consider hospital admission for patients with disabling symptoms (e.g., loss of vision, difficulty with ambulation, dysphagia). 
- Supportive care: physical therapy, occupational therapy, and/or speech and swallow evaluations
Mild exacerbations that do not impact physical functioning may not require medical treatment.
Disease-modifying MS therapy
- There are multiple disease-modifying drugs available to treat MS.
- The decision about agent requires careful consideration of:
- Individual patient's characteristics (e.g., clinical phenotype, comorbidities)
- Medication side effects
- Other factors (e.g., medication availability, route of administration)
- All patients receiving disease-modifying therapy for MS should use birth control.
|Commonly used disease-modifying MS drugs by clinical phenotype|
|Phenotype||Drugs commonly used|
|Clinically isolated syndrome |
|Relapsing-remitting MS |
|Secondary progressive MS || |
|Primary progressive MS |
Monoclonal antibodies (e.g., natalizumab, ocrelizumab) have the highest efficacy for reducing exacerbations, but lower efficacy medications (e.g., interferon beta, glatiramer acetate) often have fewer side effects. 
|Overview of disease-modifying drugs in MS therapy (DMDs) |
|Medication||Mechanism of action||Adverse effects|
|Glatiramer acetate (copolymer-1)|
|Sphingosine 1-phosphate receptor modulators ||Fingolimod|
|Monoclonal antibodies|| |
|Mitoxantrone || |
Supportive care and symptom management 
Consider any of the following measures in a management plan tailored to the individual patient:
- Encourage physical activity.
- Close follow-up with neurology and primary care
- Ancillary referral as needed (e.g., physical therapists, occupational therapists, psychologists)
- Screen for major depression and start therapy with antidepressants as needed (see also “Treatment” in “Major depression disorder”).
Urinary and bowel dysfunction
- Urinary frequency: pelvic floor physical therapy, bladder training; Consider anticholinergics (e.g., oxybutynin) and antimuscarinics (e.g., tolterodine).
- Urinary retention: Consider intermittent catheterization and (e.g., bethanechol). 
- Bowel dysfunction: dietary fiber and fluid intake; laxatives (e.g., senna) and stool softeners (e.g., docusate) as needed
- Tremors: deep brain stimulation techniques, beta blockers (e.g., propranolol), gabapentin
- Neuropathic pain: tricyclic antidepressants (e.g., amitriptyline): , other antidepressants (e.g., duloxetine), anticonvulsants (e.g., carbamazepine, gabapentin), transcutaneous electrical nerve stimulation (see also “Treatment” in “Trigeminal Neuralgia”)
- Walking difficulties: mobility aids (e.g., canes, walkers), consider dalfampridine 
- Fatigue: Consider medications such as amantadine or modafinil.
- Sexual dysfunction: Consider medications for erectile dysfunction (e.g., sildenafil) and nonpharmacological measures (e.g., vaginal lubricants, intracavernous injection therapy) as needed.
- Psychotherapy: to reduce potential psychological issues (e.g., depression)
Physical therapy, occupational therapy, and psychotherapy are safe, nonpharmacological options that can improve multiple symptoms in patients with MS, including spasticity, fatigue, walking difficulties, and neuropathic pain.
Prognostic factors for disease progression 
- Male sex
- Age at MS onset > 40 years
- Multiple symptoms with early motor and cerebellar involvement
- Incomplete recovery after exacerbations
- High relapse rate in the first 2 years after MS onset
Special patient groups
Multiple sclerosis in pregnancy 
- Effect of pregnancy on MS
Effect of MS on pregnancy
- Increased rate of elective
- Decreased birth weights 
- Most disease-modifying therapy for MS should be discontinued ≥ 4 months prior to conception. 
- Avoid steroids for the treatment of exacerbations in the first trimester of pregnancy. 
- Breastfeeding is generally not recommended for patients receiving disease-modifying therapy for MS.
- Avoid MRI with gadolinium in pregnant patients.