Multiple Sclerosis and Demyelinating Diseases 3

Question 1

Cladribine: indications, dosage

Answer 1

RRMS amd active SPMS
Indicated for the treatment of relapsing forms of multiple sclerosis, to include relapsing-remitting disease and active secondary progressive disease, in adults.
Because of its safety profile, use of MAVENCLAD is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of MS
(FDA)

Δοσολογία:
Η συνιστώμενη σωρευτική δόση είναι 3,5 mg/kg σωματικού βάρους για 2 έτη, χορηγούμενη ως 1 περίοδος θεραπείας των 1,75 mg/kg ανά έτος.
Κάθε περίοδος θεραπείας αποτελείται από 2 εβδομάδες θεραπείας, μία στην αρχή του πρώτου μήνα και μία στην αρχή του δεύτερου μήνα του αντίστοιχου έτους θεραπείας.
Εάν είναι ιατρικά απαραίτητο (π.χ. για την ανάκαμψη των λεμφοκυττάρων), η περίοδος θεραπείας κατά το έτος 2 μπορεί να καθυστερήσει για έως και 6 μήνες.
Κάθε εβδομάδα θεραπείας αποτελείται από 4 ή 5 ημέρες κατά τις οποίες ο ασθενής λαμβάνει 10 mg ή 20 mg (ένα ή δύο δισκία) ως εφάπαξ ημερήσια δόση, ανάλογα με το σωματικό βάρος.
Μετά την ολοκλήρωση των 2 περιόδων θεραπείας, δεν απαιτείται περαιτέρω θεραπεία με κλαδριβίνη κατά τα έτη 3 και 4.
Η επανέναρξη της θεραπείας μετά το έτος 4 δεν έχει μελετηθεί.

Question 2

Cladribine: mechanism of action, monitoring

Answer 2

νουκλεοσιδικό ανάλογο της δεοξυαδενοσίνης
Cytotoxic to T and B lymphocytes by impairing DNA synthesis
Typically, the nadir of lymphocyte counts occurs 2 to 3 months after the start of each treatment cycle.
Oral cladribine can penetrate the blood-CNS barrier.

Monitoring:
Before initiating each course:
* CBC including lymphocyte count (before each treatment course, 2 and 6 months after the start of each yearly course [if 2-month lymphocyte <200 cells/mm3, monitor monthly until month 6], and periodically during and after treatment);
* liver function tests (serum aminotransferase, alkaline phosphatase, and total bilirubin levels) (prior to each treatment course and as clinically appropriate).
* Evaluate HIV, tuberculosis, hepatitis B and hepatitis C status (prior to each treatment course);
* evaluate varicella zoster virus (VZV) antibody status (prior to treatment initiation). Patients who are negative to VZV antibodies should be vaccinated
* Verify pregnancy status (prior to each treatment course in patients who could become pregnant).
* MRI (at baseline [within 3 months] prior to first treatment course).

Following initiation:
- evaluate for PML
- monitor for acute infections
- follow standard guidelines for cancer screening

Question 3

Cladribine: side effects (>10%) and contraindications

Answer 3

Decreased hemoglobin
decreased platelet count
lymphocytopenia
Hypersensitivity reaction
Infection
Headache
Upper respiratory tract infection

Contraindications:
Current malignancy; pregnancy; individuals of reproductive potential who do not plan to use effective contraception during therapy and for 6 months after the last dose in each treatment course; HIV infection; active chronic infections (eg, hepatitis or tuberculosis); breastfeeding (during treatment or for 10 days after last dose)

Question 4

Vaccination and Cladribine

Answer 4

Vaccination with live or live-attenuated vaccines should be 4 weeks before therapy initiation, and these vaccines are contraindicated during oral cladribine treatment

Question 5

Cladribine: κριτήρια για έναρξη και συνέχιση θεραπείας

Answer 5

Οι αριθμοί των λεμφοκυττάρων πρέπει να είναι
* φυσιολογικοί πριν την έναρξη της θεραπείας κατά το έτος 1,
* τουλάχιστον 800 κύτταρα/mm³ πριν την έναρξη της θεραπείας κατά το έτος 2.
Εάν είναι απαραίτητο, η περίοδος θεραπείας κατά το έτος 2 μπορεί να καθυστερήσει για έως και 6 μήνες για να επιτραπεί η ανάκαμψη των λεμφοκυττάρων.
Εάν αυτή η ανάκαμψη χρειάζεται περισσότερο από 6 μήνες, ο ασθενής δεν πρέπει να λάβει δισκία κλαδριβίνης πλέον.

Question 6

Ocrelizumab: indications, dosage

Answer 6

• CIS, RRMS, active SPMS, primary progressive MS
• IV: 300 mg once on day 1, followed by 300 mg once 2 weeks later; subsequent doses of 600 mg are administered once every 6 months (beginning 6 months after the first 300 mg dose)

Question 7

Ocrelizumab: mechanism of action, monitoring, pregnancy

Answer 7

Lytic monoclonal antibody targeting CD20 molecule on surface of B cells

Monitoring:
Before initiating:
- Hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) tests (prior to therapy initiation); do not administer to patients with active hepatitis B virus confirmed by positive results for HBsAg and anti-HB tests;
- Perform latent infection screening (eg, hepatitis, tuberculosis) in high-risk populations or in countries with high tuberculosis burden (baseline).
- Monitor quantitative serum immunoglobulins (baseline, throughout treatment as clinically necessary, especially in patients with opportunistic or recurrent infections, after discontinuation of therapy until B-cell repletion).
- Assess for active infection prior to treatment.

Following initiation:
- Monitor for infusion reactions during infusion and for at least 1 hour following the end of the infusion.
- Monitor for signs/symptoms of immune-mediated colitis (evaluate promptly if colitis is suspected), infection, malignancy, and progressive multifocal leukoencephalopathy (PML).
- Perform brain MRI (at first signs/ symptoms suggestive of PML and as clinically indicated to monitor for early signs of PML).

Not recommended in pregnancy

Question 8

Ocrelizumab: side effects (>10%), contraindications

Answer 8

• Skin infection
• Decreased neutrophils, decreased serum immunoglobulins (IgM most affected)
• Infusion-related reaction
• Infection
• Upper respiratory tract infection

Contraindications: patients with active hepatitis B virus infection and those with a history of life threatening infusion reaction to ocrelizumab

Question 9

How is humoral immunity preseved in treatment with ocrelizumab?

Answer 9

Administration of ocrelizumab produces profound and sustained depletion of B cells.
Importantly, plasma cells are spared, which allows for preservation of humoral immunity.

Question 10

Ofatumumab: indications, dosage

Answer 10

• CIS, RRMS, active SPMS
• SUBQ: Initial: 20 mg once weekly for 3 doses (weeks 0, 1, and 2); maintenance: 20 mg once monthly starting at week 4

Question 11

Ofatumumab: mechanism of action, monitoring, pregnancy

Answer 11

Lytic monoclonal antibody targeting CD20 molecule on surface of B cells

Monitoring
Before initiating:
* Monitor quantitative serum immunoglobulins (at baseline, throughout treatment as clinically necessary, especially in patients with opportunistic or recurrent infections, after discontinuation of therapy until B-cell repletion);
* HBsAg, hepatitis B core antibody (HBcAb), and other hepatitis B markers as per local guidelines (baseline and as clinically necessary);
* latent infection screening (eg, hepatitis, tuberculosis) in high-risk populations or in countries with high tuberculosis burden (baseline).

Following initiation:
Monitor for signs/symptoms of PML (eg, altered mental status, motor deficits [hemiparesis or monoparesis], limb/gait ataxia, and/or vision disturbances); monitor MRI (as clinically indicated).

Not recommended in pregnancy

Question 12

Ofatumumab: side effects (>10%)

Answer 12

• Infection, serious infection
• Injection site reaction (systemic [chills, fatigue, fever, myalgia]: local: [erythema, pain, pruritus, swelling]:
• Headache

Question 13

Alemtuzumab: indications, dosage

Answer 13

• RRMS and active SPMS after suboptimal response to two or more other agents
• IV: 12 mg daily for 5 consecutive days (total 60 mg), followed 12 months later by 12 mg daily for 3 consecutive days (total 36 mg). Subsequent treatment courses of 12 mg daily for 3 consecutive days (total 36 mg) may be administered if necessary

Question 14

Alemtuzumab: mechanism of action, monitoring

Answer 14

• Monoclonal antibody that lyses cells expressing
  CD52 causing widespread and sustained depletion of lymphocytes, followed first by slow repopulation of B cells and eventually of T cells
• CBC with differential, lymphocyte subsets, LFTs, TSH, creatinine, urinalysis

Question 15

Alemtuzumab: side effects

Answer 15

• autoimmune conditions, such as immune thrombocytopenia (αυτοάνοση θρομβοπενική πορφύρα) and anti-glomerular basement membrane disease
• increased risk of malignancies, including thyroid cancer, melanoma, and lymphoproliferative disorders
• stroke
• Pruritus, skin rash, urticaria
• Thyroid disease
• Diarrhea, nausea
• Urinary tract infection
• Lymphocytopenia
• Infusion-related reaction
• Antibody development
• Fungal infection, herpes virus infection
• Fatigue, headache, insomnia
• Arthralgia, back pain, limb pain
• Nasopharyngitis, oropharyngeal pain, sinusitis, upper respiratory tract infection
• Fever

Question 16

Alemtuzumab: for which infection should prophylaxis be taken after initiation

Answer 16

Prophylaxis for herpes virus for at least 2 months or until CD4+ lymphocyte counts are 200

Question 17

Has PML ever been reported in Ocrelizumab patients?

Answer 17

Case report JAMA neurology 2021

Question 18

Which MS drugs are considered immunomodulatory and which immunosuppresing?

Answer 18

Immunomodulatory: Interferons and glatiramer acetate
They are not associated with opportunistic infections or increased cancer rates.

Immunosuppresing: Rest

Question 19

S1P receptor modulators contraindications

Answer 19

All of the S1P receptor modulators are contraindicated in any patient who within the prior 6 months had myocardial infarction, unstable angina, stroke, transient ischemic attack, or decompensated heart failure requiring hospitalization and in those with class III/IV heart failure, Mobitz type II second-degree or third-degree atrioventricular block, or sick sinus syndrome without a functioning pacemaker.

All patients should have evidence of prior varicella-zoster virus (VZV) infection or be vaccinated against VZV before initiation of an S1P receptor modulator.

Question 20

Gait and ambulatory dysfunction in MS: management

Answer 20

• Physical rehabilitation
• Bracing
• Assisting devices
• Dalfampridine

Question 21

Dalfampridine: Indications, dosage

Answer 21

• indicated for the improvement of walking in adult patients with multiple sclerosis with walking disability (EDSS 4-7)
• Oral: 10 mg every 12 hours

Question 22

Dalfampridine: Mechanism of action, pregnancy

Answer 22

• Fampyra is a potassium channel blocker.
  By blocking potassium channels, fampridine reduces the leakage of ionic current through these channels, thereby prolonging repolarization and thus enhancing action potential formation in demyelinated axons and neurological function.
  Presumably, by enhancing action potential formation, more impulses might be conducted in the central nervous system.
• Not recommended in pregrancy

Question 23

Dalfampridine: side effects >10%, contraindications

Answer 23

• Urinary tract infection

Contraindications:
* Patients with prior history or current presentation of seizure.
* Patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min).
* Concomitant use of Fampyra with medicinal products that are inhibitors of Organic Cation Transporter 2 (OCT2) for example, cimetidine

Question 24

Fatigue in MS: percentage, management

Answer 24

• Up to 78% of patients
• First treat insomnia, anxiety, depression, nocturia, spasticity, pain
• Medications: Amantadine, Modafinil, Armodafinil, Methylphenidate, SSRIs, Bupropion

Question 25

Amantadine in MS: Indications, dosage, mechanism of action

Answer 25

• Fatigue, patients who fail non-pharmacologic interventions
• Oral: 100 mg twice daily
• not known

Question 26

Amantadine in MS: Side effects (>10%), contraindications

Answer 26

• Orthostatic hypotension, peripheral edema
• Constipation, xerostomia
• Dizziness, falling, hallucination

++ less common but significant: Impulse control and related disorders, Livedo reticularis, Neuropsychiatric symptoms, Withdrawal syndrome

Contraindications:
Κύηση, γαλουχία, γνωστή υπερευαισθησία στην αμανταδίνη.

Question 27

Modafinil in MS: indications, dosage, mechanism of action

Answer 27

• Fatigue
• Oral: Initial: 100 mg/day;
  may increase daily dose based on response and tolerability in 100 mg increments at intervals ≥1 week up to 200 mg/day in 1 or 2 divided doses
• not known

Question 28

Modafinil in MS: side effects (>10%), contraindications

Answer 28

• Headache
• Decreased appetite, abdominal pain, nausea

Contraindications:
Known hypersensitivity to modafinil, armodafinil, or any component of the formulation.
Patients in agitated states or with severe anxiety; pregnancy; females who may become pregnant.

Question 29

Cognitive impairement in MS: percentage, symptoms, evaluation, management

Answer 29

• 35-65%
• abnormalities are with working memory, attention, and speed of information processing. Patients complain of memory loss, difficulties at work or with interpersonal relations, inability to multitask, and “mental fog and fatigue.”
• 1) Symbol Digit Modalities Test (SDMT) offer increased sensitivity to MS-related cognitive dysfunction.
  2) Brief Repeatable Battery of Neuropsychological Tests (BRB-N) 3) Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS)
• Modafinil can be used for symptomatic management of MS patients with severe fatigue and decreased focus

Question 30

Mood and affective disorders in MS: symptoms, management

Answer 30

Depression (the most common manifestation) lifetime risk 50%
concurrent fatigue: fluoxetine or bupropion
concurrent pain: Duloxetine
anxiety: SSRI such as escitalopram, fluoxetine, or sertraline is preferred; our preference is escitalopram
sexual dysfunction: bupropion and duloxetine
urinary incontinence and nocturia: imipramine and desipramine
excessive somnolence: venlafaxine and bupropion
Pseudobulbar affect: dextromethorphan with quinidine

For patients lacking these symptoms, initial treatment with an SSRI is a reasonable option

Question 31

Spasticity in MS: management

Answer 31

Non-pharmacological:
Rehabilitation interventions like stretching, Pilates, yoga, and functional electrical stimulation, along with weight-bearing exercises, and pool/aquatic therapy

Pharmacological:
Baclofen, Tizanidine, Botox

Question 32

Baclofen in MS: indications, dosage, mechanism

Answer 32

Spasticity

Oral:
Initial: 5 mg 3 times daily; may increase by 5 mg per dose every 3 days based on response and tolerability; maximum dose: 80 mg per day (20 mg 4 times per day).
++ Intrathecal

GABA agonist
Inhibits the transmission of both monosynaptic and polysynaptic reflexes at the spinal cord level, possibly by hyperpolarization of primary afferent fiber terminals, with resultant relief of muscle spasticity

Question 33

Baclofen in MS: side effects (>10%)

Answer 33

• Nausea, vomiting
• Asthenia, confusion, dizziness, drowsiness, headache, hypotonia

Question 34

Tizanidine in MS: indications, dosage, mechanism of action

Answer 34

• Spasticity
• Oral: Initial: 2 mg once daily usually at bedtime; may increase based on response and tolerability in increments of 2 to 4 mg per day (with a minimum of 1 to 4 days between dose increases) up to a maximum dose of 36 mg/day in 3 or 4 divided doses
• alpha2-adrenergic agonist agent which decreases spasticity by increasing presynaptic inhibition; effects are greatest on polysynaptic pathways; overall effect is to reduce facilitation of spinal motor neurons.

Question 35

Tizanidine in MS: side effects >10%

Answer 35

Xerostomia
Nervous system: Asthenia, dizziness, drowsiness

++ less common but significant: Hepatotoxicity, Hypotension, Withdrawal syndrome

Question 36

Tremor in MS: management

Answer 36

There is no useful pharmacotherapy for cerebellar tremor
The rare patient with severe intention tremor and little or no ataxia, such as sometimes occurs in MS, may be helped by deep brain stimulation of the ventral intermediate nucleus of the thalamus

Question 37

Bladder dysfunction in MS: important step before starting medication

Answer 37

Differentiating between bladder spasticity (urinary frequency, urgency, incontinence) and hypotonia (urinary hesitancy, retention, and overflow incontinence) is important before initiating therapy, because different therapies are employed for each condition.

Question 38

Bladder dysfunction in MS: management

Answer 38

sphincter dysfunction: fluid management, timed voiding, the use of a bedside commode.

urine retention: Intermittent catheterization, often self-performed

Detrussor overactivity: Oxybutinin (ασκεί απ’ ευθείας αντισπασμωδική ενέργεια στις λείες μυϊκές ίνες και αναστέλλει τη μουσκαρινική δράση της ακετυλοχολίνης)

detrusor - sphincter dyssynergia: alpha antagonist medications such as prazosin, terazosin, doxazosin, and tamsulosin

Nocturia: Desmopressin
++ for hyperreflexic bladder without outlet obstruction

neurogenic detrusor overactivity who are refractory to or intolerant of anticholinergic/antimuscarinic therapy: Botox

Detrusor overactivity that is unresponsive to botulinum toxin: sacral neuromodulation with electrical stimulation of the S3 nerve root as well as peripheral nerve stimulation of the dorsal penile or clitoral nerves and posterior tibial nerve

Surgical correction, such as augmentation of bladder capacity with an exteriorized loop of bowel, is another alternative for appropriate patients, when other measures have failed.

Question 39

Treatment of primary progressive MS

Answer 39

●For patients with PPMS who are younger (eg, age ≤55 years) or have active disease on MRI, treatment with ocrelizumab is suggested.
Ocrelizumab treatment is offered to patients with PPMS who are older and have inactive disease, but patients with these characteristics may be less likely to benefit and more likely to experience adverse effects if treated with ocrelizumab.

Other than ocrelizumab, trials of DMTs used for patients with RRMS have failed to show evidence of benefit in patients with PPMS.

Question 40

Treatment of secondary progressive MS

Answer 40

●Choosing DMT – Therapeutic options for patients with active SPMS, at least in the United States, include all DMTs approved for relapsing forms of MS.
Despite evidence that siponimod was modestly effective for reducing disability progression at six months in patients with SPMS, there is not a strong rationale for its exclusive use in SPMS, particularly when other DMTs may suppress relapses or lesions just as well

*Some of our expert contributors treat active SPMS with an approach similar to that for RRMS. For patients with a relatively low level of active disease, continuing the same DMT used during the relapsing-remitting phase of MS is often the best option.

*Other experts favor switching to siponimod for patients previously on a different DMT (eg, while being treated for RRMS).

●Suboptimal response to treatment – For patients with active SPMS who have a suboptimal response to DMT, as determined by evidence of ongoing disease activity with attacks (relapses) and/or the development of new MS lesions, switching to a different DMT is a reasonable option. However, the decision is based upon clinical experience and individual patient characteristics, as no randomized clinical trials have addressed this issue.

Question 41

When to stop DMT in SPMS

Answer 41

For patients with inactive disease (ie, no ongoing relapses or gadolinium-enhancing lesions on MRI of the brain and spinal cord) who have been nonambulatory for at least two years, it is reasonable to discuss stopping DMT

Question 42

When to consider changing high efficacy DMT because of infections

Answer 42

Question 43

Is there rebound phenomenon after discontinuing anti CD20?

Answer 43

Not evidence for the moment

Question 44

Does teriflunomide cause PML?

Answer 44

No evidence for the moment
(Maybe a case report 2018)

Question 45

Women with high disease activity who wish to become pregnant: treatment options

Answer 45

Question 46

Which treatment has indication in breastfeeding

Answer 46