What constitutes a useful diagnostic test or set of criteria?
+ a b a + b
- c d c + d
a + c b + d a + b + c + d
From these we determine the sensitivity and specificity as follows:
SENSITIVITY = a/(a+c) > 80%
SPECIFICITY = d/(b+d) > 80%
Neurobiol Aging 1998; 19:109-116.
A clinico-pathoanatomical study of multiple sclerosis diagnosis
SENSITIVITY = True+ve /(True+ve + False-ve)
Eye Department, Hvidovre Hospital, Denmark.
• Neuropathological examination of 518 consecutive patients with
clinically definite MS revealed a correct diagnosis in 485 cases (94%).
• Clinical diagnosis had been established by a neurologist in all cases.
• Erroneous diagnosis included a variety of other neurological
• Also investigated was a randomly selected series of 33 patients with a
clinical diagnosis of probable MS:
– post mortem confirmation of MS was obtained in circa 66%.
– The remainder the error pattern was similar to the above.
Engell T. Acta Neurol Scand. 1988 Jul;78(1):39-44.
Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74.
PML complicating treatment with natalizumab and IFNb-1a for MS
What is the diagnosis?
Take special care with Interferon-beta-1b:
If you might have a disorder of the immune system in which
abnormal proteins are found in the blood (monoclonal
gammopathy), you must check this with your doctor before you
use interferon beta-1b. Patients who have the rare condition
known as monoclonal gammopathy may develop problems with
their small blood vessels (capillaries) leading to shock (collapse)
which can be fatal, when they use medicines like interferon-
See also 4. Possible side effects.
Could sudden death be due to MS?
Relapsing and Remitting Multiple Sclerosis:
Pathology of the Newly Forming Lesion
Barnett & Prinea. Ann Neurol 2004;55:458–468.
Sudden death in multiple sclerosis (SUDMUS)
We need to define a new entity:
Sudden death in multiple sclerosis
Prior disease modifying treatments for MS
~50 % of PML cases
have had prior
exposure both in
Europe and US
28 cases – Clifford et al. Lancet Neurol. 2010 Apr;9(4):438-46.
42 cases – Clifford et al; AAN 2010.
Slide courtesy of David Clifford
Natalizumab PML risk stratification tool
Anti-JC virus antibody status
Prior immunosuppressant use
No Yes No Yes
Relative PML Risk
< 1 in 10,000 1 in 941 in 256 1 in 6681 in 1887
Effect of plasma exchange in accelerating natalizumab
clearance and restoring leukocyte function
Khatri et al. Neurology 2009;72:402–409
N Engl J Med 2008;359:1786-801.Coles et al. Mult Scler. 1998;4:232-8.
Humoral autoimmunity syndromes as a complication of
Alemtuzumab therapy: associated with immune
reconstitution post lymphocyte depletion
• Alemtuzumab (anti-CD52)
• Grave’s disease ~30%
• Immune-mediated thrombocytopaenia (ITP) ~2-3%
• Goodpasture’s syndrome – 3 cases
• Immune-mediated neutropaenia – 1 case
• Immune-mediated haemolytic anaemia
• Well described in other clinical settings
• AIDS & HAART
• Bone marrow transplantation
• Anti-TPO Abs and raised baseline IL21 predictive of post-
• Possibly related to imbalance between regulatory, memory and
naïve T cell reconstitution
Predicting autoimmunity following treatment of MS with alemtuzumab
• 30% of alemtuzumab-treated pts develop
autoimmune side-effects (primarily
thyroid disease and idiopathic
• Aim: To define predictive factors for
• Sera of 141 pts screened at
baseline for 8 different
A combined IL-21/IL-7 test on pre-treatment serum may be useful to identify patients at
low risk of developing autoimmunity following treatment with alemtuzumab
Jones JL, et al. ECTRIMS 2011, Amsterdam. P1009
Sensitivity NPV Specificity PPV
IL-21 alone 81 84 70 66
IL-7 alone 76 76 54 54
CCL21 alone 63 65 49 47
IL-21 or IL-7 98 97 41 55
IL-21 OR IL-7
98 91 12 45
Given that pts may elect to receive treatment based
on results of this test – most weight given to
minimizing false negative results. Combining IL-21
and IL-7 into a single test offers improved test
accuracy over IL-21 alone. CCL21 did not improve
Autoimmunity No autoimmunity
0.0 0.2 0.4 0.6 0.8 1.0
0.0 0.2 0.4 0.6 0.8 1.0
IL-21 and IL-7 levels in sera
of pts who did or did not
characteristic (ROC) curves
Teriflunomide - safety
O’Connor et al. N Engl J Med 2011;365:1293-303.
• Drug interactions
Safety = Benefits - Risks
• High unemployment rates; 50%
unemployed within 10 years of
• High divorce rates; at least double the
• MS is one of the most common causes
of neurological disability in young
• Natural history studies indicate that it
takes a median time of 8, 20, and 30
years to reach the irreversible disability
levels of EDSS 4, 6, and 7, respectively3
• Life expectancy is reduced by 5–10
EDSS and utility
show a significant inverse relationship
aUtility measures are derived from EQ-5D using the EuroQoL instrument.
bError bars depict 95% confidence intervals. Half points on EDSS are not shown on graph axis, except at EDSS 6.5.
EDSS, expanded disability status scale
1 Adapted from Orme M et al. Value In Health 2007;10:54–60;
2 WHO and MSIF http://apps.who.int/bookorders/anglais/detart1.jsp?sesslan=1&codlan=1 &codcol=15&codcch=747 Accessed October 6, 2010;
3 Confavreaux C and Compston A, Mcalpine’s multiple sclerosis, 4th edn 2005; 4 Compston A et al. Lancet 2008; 372: 1502–17
MS is a debilitating disease
• MS is serious debilitating disease
• Risk: benefits
– Tolerability vs. serious AEs
– Defined and undefined risks
– Active surveillance
– Manage risks
• LFTs and blood monitoring
• JCV serology & PLEX for PML
• VZV vaccination pre-fingolimod & SOPs for starting and
• Platelet, TFTs and urine monitoring for alemtuzumab
• Individualise treatments