Multiple Sclerosis/PGS (VPL)

Clinical and paraclinical findings

 * contain warning signs (red flags) indicative of another diagnosis - we rule out causes that better explain the symptoms
 * MS is unlikely (it is necessary to look for another disease, especially a treatable one)

or


 * they indicate MS but also a coincidence with another disease (perform tests and imaging methods to confirm the coexistence of both diseases).

Eye symptoms

 * typical - unilateral retrobulbar neuritis, pain during eye movements, partial visual impairment, central scotoma, or normal papilla findings
 * less common - bilateral retrobulbar neuritis, without pain, no perception of light, moderate prominence of the papilla without hemorrhages, posterior uveitis
 * atypical - progressive optic neuropathy, severe permanent orbital pain, permanent complete vision loss, neuroretinitis, anterior severe uveitis.

Brain stem and cerebellum

 * typically - bilateral internuclear ophthalmoplegia, ataxia and nystagmus, paresis of the abducens nerve (VI nerve), facial hypoesthesia
 * less often - unilateral internuclear ophthalmoplegia, deafness, trigeminal neuralgia (nV), paroxysmal tonic spasms
 * atypical - complete external ophthalmoplegia, vascular territorial syndrome, paresis of the oculomotor nerve (n.III), progressive sensory neuropathy of the trigeminal nerve, focal dystonia, torticollis.

Spinal cord (spinal symptoms)

 * typically - partial myelopathy, Lhermitt's sign, deafferentation on the upper limbs, impaired tactile sensation (touch), urge incontinence, erectile dysfunction, progressive asymmetric spastic paraparesis
 * less often - complete transverse myelitis, radiculopathy, areflexia, thermal sensation disorders, Brown-Sequard syndrome, stool incontinence, progressive symmetrical spastic paraplegia;
 * atypical - territorial lesion of the anterior spinal artery, cauda syndrome, acute localized segmental pain, acute urinary retention, progressive sensory ataxia.

Supratentorial region

 * typically - moderate subcortical cognitive impairment, hemiparesis;
 * less often - epilepsy, hemianopsia
 * atypical - encephalopathy (hallucinations, confusion, somnolence), cortical blindness.

Procedure in differential diagnosis

 * 1) are symptoms consistent with inflammatory demyelinating disease (mono/multifocal)
 * 2) exclusion of non-myelinating syndrome - demographic data, specific symptoms, clinical course, radiological and laboratory tests
 * 3) classification as idiopathic inflammatory demyelinating disease (according to specific symptoms, clinical course, radiological and laboratory tests);
 * 4) * it is not MS (neuromyelitis optica, acute demyelinating encephalomyelitis,... unclassified);
 * 5) * consistent with MS
 * 6) ** dissemination in time and space according to McDonald's criteria
 * 7) determining the diagnosis of a non-inflammatory demyelinating disease (if we recognize red flags, we consider an alternative diagnosis).

The most common RED FLAGS - warning findings when we are looking for another diagnosis

 * clinical findings:
 * persistent monofocal symptoms - consider a structural lesion (Chiari malformation), brain tumor
 * peripheral neuropathy - consider vitamin B12 deficiency, adrenoleukodystrophy, metachromatic leukodystrophy, Lyme disease;
 * Fulminant course - consider acute demyelinating encephalomyelitis, lymphoma, thrombocytopenic purpura;
 * Psychological changes in patients treated with natalizumab - consider progressive multifocal leukoencephalopathy
 * Kidney involvement - consider vasculitides, SLE, Fabry disease;
 * Cardiac disease, arterial hypertension - rule out cerebral infarctions (multiple), brain abscesses (with endocarditis), right-to-left heart shunt;
 * Pulmonary involvement - consider sarcoidosis, lymphomatoid granulomatosis;
 * Progressive ataxia (without other symptoms) - consider multisystem atrophy, hereditary spinocerebellar ataxia, paraneoplastic cerebellar syndrome,
 * display methods:
 * simultaneous enhancement of all lesions on MRI - consider vasculitis, lymphoma, sarcoidosis
 * persistent gadolinium enhancement + slowly enlarging lesion on MRI - consider lymphoma, glioma, vasculitis, and sarcoidosis
 * lacunar infarctions - consider hypertension, cerebral autosomal dominant arteriopathy (CADASIL), Susac syndrome
 * findings of laboratory deviations:
 * neuromyelitis optica / anti-aquaporin 4 in serum - consider neuromyelitis optica;
 * specific IgM in CSF/PCR - consider neuroborreliosis;
 * antineuronal antibodies in serum - consider paraneoplastic syndromes or autoimmune encephalitis.

McDonald's diagnostic criteria for MS (according to the 2010 revision))
Requirements for auxiliary examinations for the McDonald criteria:


 * DIS (dissemination in space):
 * on MRI >/= one T2W-weighted lesion in 2 of 4 CNS regions (periventricular, juxtacortical, infratentorial, spinal cord)
 * it is not necessary for the lesion to uptake gadolinium, if the patient has clinical spinal cord/stem syndrome, the symptomatic lesion is not counted in the lesion count.
 * DIT (dissemination in time):
 * on MRI new T2W and/or gadolinium-enhancing lesions on the next MRI against the previous one, regardless of the timing of the first scan, or the simultaneous presence of asymptomatic gadolinium-enhancing and non-enhancing lesions at any time.
 * finding in the cerebrospinal fluid:
 * positivity for 2 or more oligoclonal bands in the CSF in the alkaline region that are absent in the serum, or an elevated IgG index.

Diagnostic algorithm of multiple sclerosis

 * 1) clinically definite relapsing-remitting multiple sclerosis
 * 2) * 2/more relapses (objective evidence of >/=2 lesions, or objectively 1 lesion with acceptable anamnestic evidence of a previous attack)
 * 3) ** NO => reevaluate the diagnosis!
 * 4) ** YES => dissemination in space (=DIS) ev. dissemination over time (=DIT), positive finding in CSF (not necessary) = clinically definite MS
 * 5) * 2/more relapses, objective evidence of at least 1 lesion
 * 6) ** NO => reevaluate the diagnosis!
 * 7) ** YES => dissemination in space, or another clinical attack in another CNS localization = clinically definite MS
 * 8) single clinical episode:
 * 9) * one relapse with objective evidence of >/= 2 lesions => dissemination over time (clinically isolated syndrome with a high probability of conversion to clinically definite MS), or a second relapse
 * 10) ** NO => reassess the diagnosis (examine cerebrospinal fluid and diff.dg. tests)
 * 11) ** YES => conversion from clinically isolated syndrome to clinically definite MS
 * 12) * one relapse with objective evidence of one lesion => dissemination in space (a clinically isolated syndrome with a high probability of a version to clinically definite MS) or another clinical relapse of a different localization and at the same time dissemination in time, or a second relapse
 * 13) ** NO => reassess the diagnosis (examine cerebrospinal fluid and diff.dg. tests)
 * 14) ** YES => conversion from clinically isolated syndrome to clinically definite MS

Therapeutic algorithm of MS
Clinically isolated syndrome with probable development of MS / clinically definite relapse relapsing MS


 * first-line drugs:
 * glatimer acetate
 * IFN-beta
 * in case of imperfect response / intolerance, aggressive MS:
 * second-line drugs:
 * natalizumab (monitor any psychological changes as stated above)
 * fingolimod
 * imperfect response / intolerance:
 * other treatment options: IVIG (off label), mitoxantrone, and other alternative options
 * new drugs - dimethyl fumarate, teriflunomide, and alemtuzumab

When relapses persist and MRI activity or intolerance


 * switch - change from first-line drugs:
 * IFN-beta => increase frequency / dose
 * IFN-beta => glatimer acetate
 * glatimer acetate => IFN-beta
 * fingolimod => glatimer acetate / IFN-beta
 * natalizumab => glatimer acetate / IFN-beta
 * switch - change in second-choice drugs:
 * natalizumab => fingolimod
 * fingolimod => natalizumab

Intolerance of first-line drugs


 * IVIG in off label use.

Natalizumab/fingolimod intolerance or insufficient therapeutic response


 * mitoxantrone.

Significant MS activity without being affected by registered drugs


 * rituximab, daclizumab (so far off label), cyclophosphamide, autologous high-dose immunoablation with stem cell support.

Algorithm of managing patients for therapy with drugs affecting the course of the disease
Treated patient (evaluation within 6-12 months):


 * negative MRI => reduced frequency of monitoring
 * active MRI, positive NAbs on IFN-beta treatment
 * relapses and/or progression (active MRI) => change therapy;
 * no relapses / no progression => consideration of treatment change.

Current treatment of MS reduces the frequency of relapses, disability as well as activity and atrophy on MRI. Early initiation of therapy in clinically isolated syndrome slows down the risk of developing clinically active multiple sclerosis. The combination of clinical monitoring and MRI monitoring better reflects the treatment effect. If the effectiveness of the first-line drugs is reduced, the strategy within the first-line drugs must be changed, or in the case of a more aggressive course, the second-line drugs must be used.

Related articles

 * Multiple Sclerosis - article for undergraduate studies