This document discusses the case of a 59-year-old male with highly active multiple sclerosis (HAMS), detailing his clinical history, multiple relapses, MRI findings, and treatment failures. It highlights the use of alemtuzumab, a highly efficacious therapy recently approved in India for treating HAMS, and outlines the treatment regimen and its outcomes. The patient showed significant improvement post-therapy, with a decrease in disability status, although he continued to experience residual symptoms.

1. Alemtuzumab in Highly
Active Multiple Sclerosis
Dr Pramod Krishnan, M.D, D.M
Consultant Neurologist,
Manipal Hospital, Bengaluru

2. Introduction
• Highly active Multiple Sclerosis (HAMS) refers to a subset of MS
patients who have:
1. Frequent, severe relapses,
2. Incomplete recovery from relapses,
3. Accumulation of physical disability and cognitive deficits,
4. High burden of disease on MRI,
5. Failure of treatment with one or more disease modifying therapies.
• Treatment requires highly efficacious agents like Alemtuzumab,
which has been recently approved for us in India.

3. Case history
• 59 y/male; no comorbidities.
• In 1995, he developed optic neuritis of right eye.
• Improved completely with intravenous methyl prednisolone
(IVMP).
• In 2010, developed acute urinary retention and weakness of both
lower limbs (left weaker than the right).
• Partial recovery with IVMP.
• Not started on any DMTs.

4. Relapse in 2014
• Developed left lower limb weakness of 1-week duration, with
marked difficulty in walking requiring support.
• Incomplete evacuation of urine which required catherization.
• Spasticity and brisk DTRs in the lower limbs.
• Left lower limb power was 3/5.
• Sensory examination was normal.
• He had extensor plantar response on both sides.

5. MRI cervical spine T2 sagittal: showed
hyperintensity in the cervical cord at C6-
7 vertebral level, and in the upper dorsal
cord.
MRI cervical T1 sagittal: showed
hypointense region in the cervical cord
at C6-7 vertebral level.

6. MRI cervical spine T2 axial: showed
hyperintensity in the right cervical cord.
MRI cervical spine T2 sagittal: showed
hyperintensity in the cervical cord at C2-
3 vertebral level.

7. MRI cervical spine T2 sagittal: showed
hyperintensity in the cervical cord at C2-
3, C6-7 level, and in the upper dorsal
cord.
MRI cervical spine T1 post contrast
sagittal: showed contrast enhancement
in the lesion in the upper dorsal cord.

8. MRI brain T2F axial: showed multiple
hyperintense lesions in the
periventricular and juxtacortical regions
consistent with demyelination.
MRI brain T2F axial: showed multiple
hyperintense lesions in the
periventricular and subcortical regions
consistent with demyelination.

9. MRI brain T2F axial: showed multiple
hyperintense lesions in the subcortical
and juxtacortical white matter
consistent with demyelination.
MRI brain T2 sagittal: showed multiple
hyperintense lesions involving the
corpus callosum and periventricular
white matter (Dawson fingers).

10. Investigations
• VEP showed prolonged P100 latency in both eyes.
• CSF was positive for OCBs.
• Investigations for Sarcoidosis, CTDs, vasculitis, and NMO were
negative.
• Family history: son has RRMS since the age of 22 years, well
controlled with Dimethyl fumarate.

11. Treatment
• He showed good improvement with IVMP.
• He was started on Dimethyl Fumarate 240 mg BD.
• He had residual deficits: spasticity of both lower limbs and
minimal left lower limb weakness causing difficulty in walking. He
could walk without support.
• He required intermittent self catheterisation 2-3 times a day.

12. Relapse in 2017
• During a follow up MRI, he was noted to have multiple new MRI
lesions.
• There was no clinical worsening.
• The family was concerned that the therapy was not effective.
• Dimethyl fumarate was changed to Teriflunomide 14 mg OD.

13. Relapse in 2018
• Developed acute unsteadiness of gait and urinary retention.
• New lesions were noted in the pons and cerebellar peduncle, and
in the cervical and dorsal cord.
• He improved with IVMP. He required more support to walk.
• Change of treatment was considered: Rituximab, Natalizumab
and Alemtuzumab. Family was undecided.
• Teriflunomide was continued.

14. Relapse in Jan 2019
• Acute bowel and urinary urgency, frequency and urge
incontinence.
• Unsteadiness of gait with inability to stand or walk even with
support.
• He had right lower limb weakness, with spasticity, power of 3/5
with extensor plantar response.
• Pre-existing left lower limb weakness worsened.
• New lesions were noted in the MRI brain and spine.

15. MRI brain T2F axial: showed multiple
hyperintense lesions in the
periventricular and subcortical regions
consistent with demyelination.
MRI brain T2F axial: showed multiple
hyperintense lesions in the subcortical
and juxtacortical white matter
consistent with demyelination.

16. MRI brain T2F axial: showed multiple
hyperintense lesions in the juxtacortical
white matter consistent with
demyelination.
MRI brain T2F axial: showed multiple
hyperintense lesions in the
periventricular and subcortical regions
consistent with demyelination.

17. MRI brain T2F axial: showed left cerebellar hemisphere hyperintense lesion consistent with
demyelination.

18. Treatment
• Even though he improved significantly with IVMP, the symptoms
relapsed on tapering the oral steroids.
• He needed intermittent self catheterisation and daily laxatives,
and mobility was possible only with a walker.

19. Poor prognostic factors
In this patient In General
Older age at onset Multifocal onset
Male sex High relapse rate in the first two years.
Efferent system involvement (motor,
cerebellar, sphincter)
Disability after 5 years.
Partial or no recovery from a relapse Brain atrophy
MRI showing large lesion load. Neurofilament light chain (NfL)
Posterior fossa lesions
CSF positive for OCB
Efficacy and safety data for patients above 55 years of age is not available.

20. Treatment
• In view of frequent relapses, incomplete recovery, increasing MRI
lesions, and failure of dimethyl fumarate and Teriflunomide, he
was offered treatment with a highly efficacious agent like
Natalizumab, Alemtuzumab or Rituximab.
• The patient opted for Alemtuzumab.

21. Alemtuzumab Proposed Mechanism of Action: Targeting of T and B Cells
1. Selection1,2 2. Depletion1,2 3. Repopulation1,2
BT
T cell
precursor
Pre/Pro
B cell
Lymphocyte
precursor
Stem cell
BT
Plasma
Cells
Monocytes
Macrophages
Neutrophils
Lymphocyte
precursor
Lymphocyte
precursor
CD52
CD52
B
T
CD52
CD52
B
T
• Alemtuzumab is a monoclonal antibody directed at the CD52 surface
antigen expressed highly on T and B lymphocytes1,3
• Innate immune cells that express lower levels of CD52 are minimally or
transiently impacted by alemtuzumab treatment1,3
CD52

22. Preparation for Alemtuzumab therapy
• Teriflunomide was stopped 3 weeks prior to therapy.
• Screening for TB with Quantiferon Gold test and Chest X-ray.
• Vaccination against Varicella Zoster atleast 6 weeks prior to
therapy, if there is h/o chicken pox, or vaccination in the past.
• In view of his age he was also vaccinated against Influenza and
Pneumococcus.
• A 28 day course of Acyclovir 200 mg BD was started on the night
prior to Alemtuzumab therapy.
• Ensure there is no active infection.

23. Alemtuzumab: Dosage and Administration
Initial treatment course:
• 12 mg/day for 5 consecutive days (60 mg total dose)
Second treatment course (after 12 months):
• 12 mg/day for 3 consecutive days (36 mg total dose).
Retreatment:
• 12 mg/day for 3 consecutive days, after 24 months of last dose, if
indicated.

24. Treatment protocol: Pre-medications
Premedications
Inj Ondansetron 4 mg IV q8h
Inj Ranitidine 50 mg or Pantoprazole 40 mg IV stat.
Inj Pheniramine 45 mg (1 ampoule, 2 ml) IV stat.
Inj Paracetamol 1000 mg in 100 ml NS infusion over 30 minutes.
Inj Methyl prednisolone 1000 mg in 100 ml NS infusion over 90-120 min (first 3 days)
NS at 20-25 ml/hr through the main port during the Alemtuzumab infusion.

25. Treatment Protocol: Alemtuzumab
Alemtuzumab therapy
Inj Alemtuzumab 12 mg (1.2 ml) IV infusion in 100 ml NS or 5% dextrose over 4-5
hours (not to exceed 8 hrs) daily for 5 days.
It is supplied as a clear liquid. Do not use if there is any particulate matter or
discoloration.
Do not shake Alemtuzumab vial. Mix in NS bottle by gently inverting it repeatedly.
Protect the infusion apparatus from light.
Connect NS to the primary port so that the IV line patency is maintained.
Alemtuzumab is administered through the side port.
If another medicine is to be administered, the Alemtuzumab port should be closed.
Monitor BP, pulse, SaO2 every 30 min during infusion, and thereafter, hourly for 2
hours.

26. Course
• Alemtuzumab infusion was uneventful except for high BP from
day 3 onwards.
• Required multiple antihypertensives. BP returned to normal
during follow up and antihypertensives were discontinued.
• Was discharged on Day 6.
• Advised to avoid crowded areas and to ensure personal hygiene
and cleanliness in the house.
• Normal diet and indoor activities.
• Outdoor activities involving interaction with multiple people was
restricted for around 1 month.

27. Follow up
• No fresh symptoms.
• Able to walk without support, but slow. Uses a walker for faster
mobility.
• Urinary symptoms have subsided. No need for catherization.
• Bowel movements are normal, without laxatives.
• Has significant spasticity of both lower limbs and mild weakness
of left lower limb.

28. Disability over the years (EDSS)
Year EDSS
2014 6.5 following the relapse, improved to 6.0
2015 6.0
2016 6.0
2017 6.0
2018 6.5 following the relapse, improved to 6.0
2019 Worsened to 6.5 after the relapse,
After Alemtuzumab, improved to 5.5 at 3.5 months
follow up.
Expanded Disability Status Scale (EDSS)

29. Risks identified in clinical trials
Alemtuzumab is not registered in any of the MENA COUNTRIES

30. Long term monitoring
• CBC, Urine routine and serum creatinine every month for 4 years.
• Thyroid function tests should be done every 3 months for 4 years.
• MRI brain and Spine every 6 months in the first year, and once a
year thereafter.
• Annual HPV screening for female patients.

31. Conclusion
• Highly active MS is uncommon and is characterised by frequent
relapses, incomplete recovery, high lesion burden on imaging, and
poor response to first line DMTs.
• Alemtuzumab can be safely used in patients with highly active
multiple sclerosis.
• Even patients with significant disability and adverse prognostic
factors may benefit.