Multiple Sclerosis
Lecture: Clinical Introduction of MS
1st of November
Globally, there are 2-3 million people with MS. 1-2 out of 1000 in the NL have MS. Most MS
patients are females. The typical age of onset is between 20-40 years. It is a western disease
and thus it is more prevalent in Europe, America and Australia. This might be related to Vitamin
D availability (the lower the VitD levels, the more susceptible people are to MS).
MS is a disease of the CNS (brain and spinal cord), not a muscle disease. There are 2 main
pathological processes:
1. Demyelination: axons of CNS neurons lose their myelin (breakdown of myelin and
oligodendrocytes). It is considered to be an inflammatory process with inflammatory
lesions, which can be modulated with immunomodulatory drugs. Given that the myelin is
broken down, signals cannot transport very well across the axons.
These demyelinating, inflammatory lesions can be easily seen with MRI. It is important to know
where these lesions are and how they look. Not all patients have lesions.
2. Neuronal degeneration: progression of disabilities with neuronal loss, leading to atrophy
(brain gets smaller). This process cannot be slowed down or stopped.
The causes of MS are not known: is it an auto-immune disorder or does something else occur
in the brain, making the immune cells go there?
!"#$%&'()*+#%'+,-%.,/,)"(#%0(1'/(,#%"/(+,'#,%21,/%3,*34,%"/%5*6+%&'7"45%1'8,%")9:%,/8"+*/7,/)'4%
&'()*+#% 0;3#),"/<='++% 8"+6#% >% '44% ?@% 3')",/)#% 1'8,% ;=A:% 4*2% 8")'7"/% B% 4,8,4#:% #7*$"/.:% ,'+45%
*C,#")59D
Most MS patients experience relapses (semi-acute attacks of neurological symptoms), in which
symptoms increase and after some weeks/months, symptoms gradually disappear).
- Optic neuritis-%*3)"('4%/,+8,%.,)#%"/&4'7,E%'/E%E,75,4"/'),E%>%3')",/)#%#4*245%,F3,+",/(,%
8"#6'4% 4*##% "/% */,% ,5,:% 2")1% E,(+,'#,E% 8"#6'4% '(6")5:% ,#3,("'445% "/% (,/)+'4% 8"#6'4% &",4E#D%
G1,+,%"#%'4#*%3'"/%C,1"/E%)1,%,5,%'/E%8"#"*/%2")1%4,##%(*4*+#D
- Double vision: due to MS lesions on the brain stem interfering with the eye movement
nerves.
- Lhermitte’s symptoms-% #3"/'4% (*+E% 3+*C4,7#% 21,/% )1,+,% '+,% 4,#"*/#% */% )1,% (,+8"('4%
#3"/'4%(*+E%>%2'4$"/.%E"#'C"4")",#%'/E%#,/#*+5%3+*C4,7#D%H')",/)#%&,,4%,4,()+"('4%#,/#')"*/#%
21,/%)1,5%7*8,%)1,"+%1,'E%&*+2'+ED%
1
, - Motor function issues-%21,/%)1,+,%'+,%4,#"*/#%"/%)1,%#3"/'4%(*+E:%4,#"*/#%2"44%C,%C"<4'),+'4%
>%3+*C4,7#%2")1%2'4$"/.D%I'4$"/.%4,/.)1#%C,(*7,%#1*+),+D%
- Bladder dysfunction: urgent incontinence and sexual dysfunction.
- Psychological functions-%(*./")"8,%"##6,#%>%3')",/)#%('//*)%764)")'#$%'/57*+,D%G1,+,%"#%
'4#*%')),/)"*/%E,&"("):%7,7*+5%'/E%4'/.6'.,%3+*C4,7#D%
- Fatigue.
MS can start off as relapse-remitting MS (80% of patients), which is characterized by relapses
and inflammatory lesions on the MRI. If nothing is done, over the years patients will experience
gradual deterioration and disability progression. In secondary progressive MS, patients do not
have relapses, only deterioration of the neurological function.
10-15% of patients start off with primary progressive MS (no relapses, only gradual
deterioration of neurological functions).
Active MS occurs when patients have relapses and new lesions can be seen on the MRI.
Progressive occurs when patients gradually deteriorate.
Diagnosis of MS is based on the patient’s situation. If it is the first episode and the patient does
not fit the criteria, then it is a clinically isolated syndrome (CIS). The criteria for MS diagnosis is
based on dissemination in space and time.
- Dissemination in space-%2,%2'/)%)*%#,,%4,#"*/#%*/%)1,%?!J%*&%)1,%C+'"/%'/E%#3"/'4%(*+E#%
"/%)2*%)53"('4%'+,'#%'/E%2'5#%>%4,#"*/#%76#)%C,%*8'4%'/E%3,+3,/E"(64'+%)*%)1,%8,/)+"(4,#%
'/E%'EK'(,/)%)*%)1,%(*+),F:%"/%)1,%(,+,C,4467:%C+'"/%#),7%*+%#3"/'4%(*+ED%L,#"*/#%#1*64E%
C,%"/%')%4,'#)%)2*%4*(')"*/#D%
- Dissemination in time: lesions should be evident in at least two time points and in more
than one relapse, shown in the MRI. When new lesions are shown, this means that the
disease is progressing. Contrast in the MRI shows the new lesions that were formed
(these are contrast-enhancing lesions). Non-contrast enhancing lesions are older
lesions.
- B,),()"*/% *&% )1,% 3+,#,/(,% *&% *4".*(4*/'4% C'/E#% "/% )1,% (,+,C+'4<#3"/'4% &46"E% 8"'% '% 467C'+%
36/()6+,D%@,,%21,)1,+%)1,+,%'+,%"776/*.4*C64"/#%"/%)1,%(,+,C+'4<#3"/'4%&46"E%>%J.M<"/E,F%
"/%)1,%*4".*(4*/'4%C'/E#D%
N/(,%E"'./*#"#%"#%7'E,:%)1,%3')",/)%76#)%C,%&*44*2,E<63%&*+%'/5%E"#,'#,%3+*.+,##"*/:%+,4'3#,#%
'/E%"/8"#"C4,%#573)*7#D%?!J%#('/#%'+,%'42'5#%7'E,%)*%#,,%21,)1,+%)1,+,%'+,%/,2%4,#"*/#%'/EO*+%
C+'"/%')+*315D%P,2%C"*7'+$,+#%0/,6+*<&"4'7,/)%4".1)%>%&+*7%)1,%C+*$,/%E*2/%'F*/#9%('/%'4#*%C,%
6#,ED
2
,Lecture: MS and therapy
1st of November
MS is widely characterized by the local inflammation of the brain and spinal cord. All MS drugs
prevent active white matter demyelination and thus prevent new inflammation from
happening. This is the immunomodulation area of MS therapy. The types of MS therapy are:
- Exacerbations: treatments of symptoms during exacerbations. Steroids are given
intravenously.
- Symptomatic treatment: treatment of spasticity, urinary incontinence and pain.
- Immunomodulation: treatment to prevent relapses.
Back then (in 2002), only a few drugs were available to treat MS. Treatment was given very late,
only when you were sure that the patient had MS, with numerous debilitating MS symptoms. The
side-effects and long-term effects of these drugs were also not known.
Nowadays, since there is a huge list of compounds that can be used, MS treatment starts right
after diagnosis and the first clinical complaint. This is done to prevent new inflammatory relapses
from happening. This is the 1st line of therapy. There is also the high-efficacy 2nd line of
therapy. 2nd line therapy is used when the 1st line therapy compounds are not efficient in
controlling the focal inflammation.
Patients should be treated sooner and more aggressively to prevent more neurological
disabilities from happening (in the form of relapses and exacerbations). The patient should also
be fully stabilized and monitored by MRI scans. Note that MS drugs are very expensive. The
costs increase after each therapy year.
Patient X is 28 years old. His/her disease history is the following:
- 2007: patient had optic neuritis, but no lesions were shown on the MRI scan. Treatment
was not given and his/her visual disturbance fully resolved spontaneously. Patient was
stable for 2 years, without complaints.
- 2009: sensory disturbances appeared on his/her right hand, also difficulty in writing.
Medication: none.
Family history: negative for MS.
No relevant comorbidities.
A new MRI-scan was made: lesions could be clearly seen:
Thus: patient X has presented complaints over time (dissemination
in time) and there is also dissemination in space (MRI lesions are
shown in at least 2 locations). Thus, the diagnosis of MS can be made.
In addition, in 2009, a presence of oligoclonal bands in the cerebral-spinal fluid was detected.
This is an additional argument for the diagnosis of MS, though it is not needed.
3
, Before starting treatment, the patient must choose what
type of medication they want. A few aspects should be
taken into account:
- Effectiveness vs risk (side-effects): short term vs
long term.
- Mode of administration.
- Costs.
Goal of therapy with any compound is to treat early to prevent any new disabilities from
happening at the early and late disease stage. There is a lower risk of secondary disease
progression if treatment is given soon. Thus: treat as soon as diagnosis is made so that you can
delay the accumulation of irreversible neurologic damage and consequent disability.
The effectiveness of the drugs aims in reducing the focal inflammation. Studies have shown
that there is a reduction of inflammation compared to placebo. The less the effectiveness of the
drugs, the lower the risk for serious side-effects. On the other hand, effective drugs have a higher
risk for serious side-effects.
1st line therapy options are drugs with low efficacy but also with a lower side-effect risk. Side
effects for this line of therapy include flu-like reactions. 2nd line therapy options are drugs with
higher efficacy but with greater risk for side-effects, which could be severe brain infection.
Each drug has a different mechanism or mode of action, and all of them work as an
immunomodulating drug (prevention of relapses/inflammation).
The 4 most used drug compounds in 1st line therapy are:
- Interferons-beta-%)1,+,%'+,%Q%E"&&,+,/)%JRPC%3+*E6()#:%C6)%)1,5%'44%2*+$%#"7"4'+45:%'/E%)1,5%
'44%1'8,%)1,%#'7,%,&&"('(5%>%'+*6/E%STU%+,E6()"*/%*&%+,4'3#,#D%G1,5%'+,%#,4&<"/K,()'C4,%
0V%E*#,%'%2,,$9D%J)%('/%C,%6#,E%E6+"/.%3+,./'/(5%'/E%C+,'#)<&,,E"/.D%G1,%7*#)%(*77*/%
#"E,%,&&,()#%'+,%#$"/%+,'()"*/#:%&46<4"$,%#573)*7#%>%,'(1%'##*("'),E%2")1%E,8,4*37,/)%*&%
/,6)+'4"W"/.%'/)"C*E",#D%
- Glatiramer acetate (copaxone): pool of peptides composed of random sequences of 4
amino acids. Given as a daily injection. Efficacy is around 30% in reducing relapses. Side
effects include skin reactions.
- Dimethyl Fumarate: first oral compound. Side effects include gastro-intestinal events,
flushing and brain infection (PML - progressive multifocal leukoencephalopathy). The
latter is a rare side-effect in patients that have a low lymphocyte count while using it.
- Teriflunomide: oral compound. Wide range of side-effects: nausea, diarrhea, hair
thinning or decreased hair density.
All these 4 compounds are equally effective (30%). Depends on which side-effects the patient is
willing to stand. Combinations are not possible. Long-term side effects are not always known.
Some drugs were only put out in the market in the last few years. Some patients choose the
well-known compounds, such as IFNb and copaxone, because they do not know the long-term
effects of the newer drugs.
4
Lecture: Clinical Introduction of MS
1st of November
Globally, there are 2-3 million people with MS. 1-2 out of 1000 in the NL have MS. Most MS
patients are females. The typical age of onset is between 20-40 years. It is a western disease
and thus it is more prevalent in Europe, America and Australia. This might be related to Vitamin
D availability (the lower the VitD levels, the more susceptible people are to MS).
MS is a disease of the CNS (brain and spinal cord), not a muscle disease. There are 2 main
pathological processes:
1. Demyelination: axons of CNS neurons lose their myelin (breakdown of myelin and
oligodendrocytes). It is considered to be an inflammatory process with inflammatory
lesions, which can be modulated with immunomodulatory drugs. Given that the myelin is
broken down, signals cannot transport very well across the axons.
These demyelinating, inflammatory lesions can be easily seen with MRI. It is important to know
where these lesions are and how they look. Not all patients have lesions.
2. Neuronal degeneration: progression of disabilities with neuronal loss, leading to atrophy
(brain gets smaller). This process cannot be slowed down or stopped.
The causes of MS are not known: is it an auto-immune disorder or does something else occur
in the brain, making the immune cells go there?
!"#$%&'()*+#%'+,-%.,/,)"(#%0(1'/(,#%"/(+,'#,%21,/%3,*34,%"/%5*6+%&'7"45%1'8,%")9:%,/8"+*/7,/)'4%
&'()*+#% 0;3#),"/<='++% 8"+6#% >% '44% ?@% 3')",/)#% 1'8,% ;=A:% 4*2% 8")'7"/% B% 4,8,4#:% #7*$"/.:% ,'+45%
*C,#")59D
Most MS patients experience relapses (semi-acute attacks of neurological symptoms), in which
symptoms increase and after some weeks/months, symptoms gradually disappear).
- Optic neuritis-%*3)"('4%/,+8,%.,)#%"/&4'7,E%'/E%E,75,4"/'),E%>%3')",/)#%#4*245%,F3,+",/(,%
8"#6'4% 4*##% "/% */,% ,5,:% 2")1% E,(+,'#,E% 8"#6'4% '(6")5:% ,#3,("'445% "/% (,/)+'4% 8"#6'4% &",4E#D%
G1,+,%"#%'4#*%3'"/%C,1"/E%)1,%,5,%'/E%8"#"*/%2")1%4,##%(*4*+#D
- Double vision: due to MS lesions on the brain stem interfering with the eye movement
nerves.
- Lhermitte’s symptoms-% #3"/'4% (*+E% 3+*C4,7#% 21,/% )1,+,% '+,% 4,#"*/#% */% )1,% (,+8"('4%
#3"/'4%(*+E%>%2'4$"/.%E"#'C"4")",#%'/E%#,/#*+5%3+*C4,7#D%H')",/)#%&,,4%,4,()+"('4%#,/#')"*/#%
21,/%)1,5%7*8,%)1,"+%1,'E%&*+2'+ED%
1
, - Motor function issues-%21,/%)1,+,%'+,%4,#"*/#%"/%)1,%#3"/'4%(*+E:%4,#"*/#%2"44%C,%C"<4'),+'4%
>%3+*C4,7#%2")1%2'4$"/.D%I'4$"/.%4,/.)1#%C,(*7,%#1*+),+D%
- Bladder dysfunction: urgent incontinence and sexual dysfunction.
- Psychological functions-%(*./")"8,%"##6,#%>%3')",/)#%('//*)%764)")'#$%'/57*+,D%G1,+,%"#%
'4#*%')),/)"*/%E,&"("):%7,7*+5%'/E%4'/.6'.,%3+*C4,7#D%
- Fatigue.
MS can start off as relapse-remitting MS (80% of patients), which is characterized by relapses
and inflammatory lesions on the MRI. If nothing is done, over the years patients will experience
gradual deterioration and disability progression. In secondary progressive MS, patients do not
have relapses, only deterioration of the neurological function.
10-15% of patients start off with primary progressive MS (no relapses, only gradual
deterioration of neurological functions).
Active MS occurs when patients have relapses and new lesions can be seen on the MRI.
Progressive occurs when patients gradually deteriorate.
Diagnosis of MS is based on the patient’s situation. If it is the first episode and the patient does
not fit the criteria, then it is a clinically isolated syndrome (CIS). The criteria for MS diagnosis is
based on dissemination in space and time.
- Dissemination in space-%2,%2'/)%)*%#,,%4,#"*/#%*/%)1,%?!J%*&%)1,%C+'"/%'/E%#3"/'4%(*+E#%
"/%)2*%)53"('4%'+,'#%'/E%2'5#%>%4,#"*/#%76#)%C,%*8'4%'/E%3,+3,/E"(64'+%)*%)1,%8,/)+"(4,#%
'/E%'EK'(,/)%)*%)1,%(*+),F:%"/%)1,%(,+,C,4467:%C+'"/%#),7%*+%#3"/'4%(*+ED%L,#"*/#%#1*64E%
C,%"/%')%4,'#)%)2*%4*(')"*/#D%
- Dissemination in time: lesions should be evident in at least two time points and in more
than one relapse, shown in the MRI. When new lesions are shown, this means that the
disease is progressing. Contrast in the MRI shows the new lesions that were formed
(these are contrast-enhancing lesions). Non-contrast enhancing lesions are older
lesions.
- B,),()"*/% *&% )1,% 3+,#,/(,% *&% *4".*(4*/'4% C'/E#% "/% )1,% (,+,C+'4<#3"/'4% &46"E% 8"'% '% 467C'+%
36/()6+,D%@,,%21,)1,+%)1,+,%'+,%"776/*.4*C64"/#%"/%)1,%(,+,C+'4<#3"/'4%&46"E%>%J.M<"/E,F%
"/%)1,%*4".*(4*/'4%C'/E#D%
N/(,%E"'./*#"#%"#%7'E,:%)1,%3')",/)%76#)%C,%&*44*2,E<63%&*+%'/5%E"#,'#,%3+*.+,##"*/:%+,4'3#,#%
'/E%"/8"#"C4,%#573)*7#D%?!J%#('/#%'+,%'42'5#%7'E,%)*%#,,%21,)1,+%)1,+,%'+,%/,2%4,#"*/#%'/EO*+%
C+'"/%')+*315D%P,2%C"*7'+$,+#%0/,6+*<&"4'7,/)%4".1)%>%&+*7%)1,%C+*$,/%E*2/%'F*/#9%('/%'4#*%C,%
6#,ED
2
,Lecture: MS and therapy
1st of November
MS is widely characterized by the local inflammation of the brain and spinal cord. All MS drugs
prevent active white matter demyelination and thus prevent new inflammation from
happening. This is the immunomodulation area of MS therapy. The types of MS therapy are:
- Exacerbations: treatments of symptoms during exacerbations. Steroids are given
intravenously.
- Symptomatic treatment: treatment of spasticity, urinary incontinence and pain.
- Immunomodulation: treatment to prevent relapses.
Back then (in 2002), only a few drugs were available to treat MS. Treatment was given very late,
only when you were sure that the patient had MS, with numerous debilitating MS symptoms. The
side-effects and long-term effects of these drugs were also not known.
Nowadays, since there is a huge list of compounds that can be used, MS treatment starts right
after diagnosis and the first clinical complaint. This is done to prevent new inflammatory relapses
from happening. This is the 1st line of therapy. There is also the high-efficacy 2nd line of
therapy. 2nd line therapy is used when the 1st line therapy compounds are not efficient in
controlling the focal inflammation.
Patients should be treated sooner and more aggressively to prevent more neurological
disabilities from happening (in the form of relapses and exacerbations). The patient should also
be fully stabilized and monitored by MRI scans. Note that MS drugs are very expensive. The
costs increase after each therapy year.
Patient X is 28 years old. His/her disease history is the following:
- 2007: patient had optic neuritis, but no lesions were shown on the MRI scan. Treatment
was not given and his/her visual disturbance fully resolved spontaneously. Patient was
stable for 2 years, without complaints.
- 2009: sensory disturbances appeared on his/her right hand, also difficulty in writing.
Medication: none.
Family history: negative for MS.
No relevant comorbidities.
A new MRI-scan was made: lesions could be clearly seen:
Thus: patient X has presented complaints over time (dissemination
in time) and there is also dissemination in space (MRI lesions are
shown in at least 2 locations). Thus, the diagnosis of MS can be made.
In addition, in 2009, a presence of oligoclonal bands in the cerebral-spinal fluid was detected.
This is an additional argument for the diagnosis of MS, though it is not needed.
3
, Before starting treatment, the patient must choose what
type of medication they want. A few aspects should be
taken into account:
- Effectiveness vs risk (side-effects): short term vs
long term.
- Mode of administration.
- Costs.
Goal of therapy with any compound is to treat early to prevent any new disabilities from
happening at the early and late disease stage. There is a lower risk of secondary disease
progression if treatment is given soon. Thus: treat as soon as diagnosis is made so that you can
delay the accumulation of irreversible neurologic damage and consequent disability.
The effectiveness of the drugs aims in reducing the focal inflammation. Studies have shown
that there is a reduction of inflammation compared to placebo. The less the effectiveness of the
drugs, the lower the risk for serious side-effects. On the other hand, effective drugs have a higher
risk for serious side-effects.
1st line therapy options are drugs with low efficacy but also with a lower side-effect risk. Side
effects for this line of therapy include flu-like reactions. 2nd line therapy options are drugs with
higher efficacy but with greater risk for side-effects, which could be severe brain infection.
Each drug has a different mechanism or mode of action, and all of them work as an
immunomodulating drug (prevention of relapses/inflammation).
The 4 most used drug compounds in 1st line therapy are:
- Interferons-beta-%)1,+,%'+,%Q%E"&&,+,/)%JRPC%3+*E6()#:%C6)%)1,5%'44%2*+$%#"7"4'+45:%'/E%)1,5%
'44%1'8,%)1,%#'7,%,&&"('(5%>%'+*6/E%STU%+,E6()"*/%*&%+,4'3#,#D%G1,5%'+,%#,4&<"/K,()'C4,%
0V%E*#,%'%2,,$9D%J)%('/%C,%6#,E%E6+"/.%3+,./'/(5%'/E%C+,'#)<&,,E"/.D%G1,%7*#)%(*77*/%
#"E,%,&&,()#%'+,%#$"/%+,'()"*/#:%&46<4"$,%#573)*7#%>%,'(1%'##*("'),E%2")1%E,8,4*37,/)%*&%
/,6)+'4"W"/.%'/)"C*E",#D%
- Glatiramer acetate (copaxone): pool of peptides composed of random sequences of 4
amino acids. Given as a daily injection. Efficacy is around 30% in reducing relapses. Side
effects include skin reactions.
- Dimethyl Fumarate: first oral compound. Side effects include gastro-intestinal events,
flushing and brain infection (PML - progressive multifocal leukoencephalopathy). The
latter is a rare side-effect in patients that have a low lymphocyte count while using it.
- Teriflunomide: oral compound. Wide range of side-effects: nausea, diarrhea, hair
thinning or decreased hair density.
All these 4 compounds are equally effective (30%). Depends on which side-effects the patient is
willing to stand. Combinations are not possible. Long-term side effects are not always known.
Some drugs were only put out in the market in the last few years. Some patients choose the
well-known compounds, such as IFNb and copaxone, because they do not know the long-term
effects of the newer drugs.
4
