MasterClass 4.1 Case Studies Session 1
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1 MasterClass 4.1 Case Studies Session 1
2 Delegate case Case of 30 year old Caucasian lady with relapsing short segment cervical myelitis (2 episodes in last year) with good response to steroids. MRI brain, VEPs, antibodies normal with positive OCBs.
3 Case 1
4 34-yr old right handed male December 99 tingling tips of great toes April 2000 found to anaemic as a screen during blood donation Mild anaemia Hb 11 g/dl, normachromic normocytic anaemia VB12 and folate low normal Sensory symptoms gradually progressed to involve feet Referred to neurosurgeon Abnormal MRI Referred him to a neurologist who made a diagnosis of probable MS
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7 Diagnosis Subacute combined degeneration of spinal cord vb12 supplementation No improvement Referred to haematologists Bone marrow showed dysplastic marrow (non-specific) VEP s Bilaterally delayed (P100 ~ 125msecs)
8 Diagnosis Multiple sclerosis
9 Jan 2002 Myelopathy sensory ataxia mild pyramidal signs. Optic neuropathy VA 6/9 & 6/12, abnormal colour vision and pale discs Neuropathy glove and stocking sensory loss with depressed ankle jerks FH (adopted) Non-smoker, Alcohol 14-21u/week Banker working in the city, married, two children MRI C-spine signal change had become more extensive
10 Jan 2002 Bloods Hb 8.9 g/dl (microcytic), neutrophils 1.2, platelets 95 TFTs, U&E, LFTs, ESR, CRP, ANF, vb12, folate, HTLV-1&2, ve, lactate, pyruvate normal or negative. Transcobalamin 1, homocysteine and urinary malonic acids normal. Plasma and urine organic acid profile were normal. White cell enzymes normal Iron 3.6 (low), TIBC 90 (45-70), Fe-binding sat. 4% (45-70), ferritin 151 (normal) important result. CSF normal VEP s delayed SEPs abnormal NCS absent SNAPs normal motor conduction studies severe sensory neuronopathy
11 Clinical phenotype Optic neuropathy demyelinating Myelopathy motor & sensory Sensory Neuronopathy Bone marrow dysplasia Fe block unable to mobilise Fe from peripheral stores.
12 Diagnostic results Serum copper = 0.7 umol/l) Caeruloplasmin <0.02 Serum zinc 32.4 umol/l (11-18 umol/l) Penicillamine challenge normal urinary copper excretion Zinc toxicity with secondary copper deficiency
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20 Case 2
21 34-yr old afro Caribbean female Presented with episode of acute myelitis with quadraparesis 3 months later episode of typical left acute optic neuritis with with 6/60 vision MRI brain 2 non-specific white matter lesions? Multiple Sclerosis
22 34-yr old afro Caribbean female 34-yr old afro Caribbean female presented with episode of acute myelitis with quadraparesis Longitudinally extensive spinal lesion (>3 vertebral segments) active CSF with 75 lymphocytes -ve OCBs MRI brain 2 non-specific white matter lesions Poor recovery of next 3 months 3 month later episode of typical left acute optic neuritis with with 6/60 vision Poor recovery 6/24 after 12 months 24 months later Coomb s positive haemolytic anaemia Positive ANF titre of 1:320 Positive anti-dsdna? Multiple Sclerosis
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25 Case 3
26 44-yr old woman Lab technician at Queen Square contacts me for advice regarding her aunt who lived in the midlands: 44-yr old Caucasian woman with a 9-year history of primary progressive MS (progressive spastic paraparesis) Admitted to peripheral hospital with persistent vomiting and low blood pressure ITU were having difficulty maintaining her blood pressure What is the diagnosis?
27 Adrenomyeloneuropathy Female adrenoleukodystrophy phenotypes Phenotype Description Onset Approximate Relative Frequency Asymptomatic No neurologic or adrenal involvement Most women under 30 do not have any neurologic involvement Diminishes with age Mild myelopathy Moderate to severe myeloneuropathy Cerebral involvement Adrenal involvement Increased deep tendon reflexes, sensory changes in lower extremities Similar to male AMN phenotype, but later onset and milder presentation Progressive dementia and decline Adulthood Adulthood Rare in childhood, more common in adults Approximately 50% of women over 40 years of age Approximately 15% of women over 40 years of age ~2% Primary adrenal insufficiency Any age ~1% Moser et al. (2001)."131. X-Linked Adrenoleukodystrophy". In Scriver, et al B. Metabolic and Molecular Bases of Inherited Disease
28 Case 4
29 PML complicating treatment with natalizumab and IFNb-1a for MS Kleinschmidt-DeMasters,et al. N Engl J Med Jul 28;353(4):
30 PML complicating treatment with natalizumab and IFNb-1a for MS Kleinschmidt-DeMasters,et al. N Engl J Med Jul 28;353(4):
31 The evolving clinical definition of MS 1. Schumacher, et al. Problems of Experimental Trials of Therapy in Multiple Sclerosis: Report by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann N Y Acad Sci 1965;122: Poser, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13: McDonald, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50: Polman, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol 2005;58: Polman, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:
32 What constitutes a useful diagnostic test or set of criteria? TARGET DISORDER PRESENT ABSENT DIAGNOSTIC TEST RESULT + 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:
33 A clinico-pathoanatomical study of MS diagnosis SENSITIVITY = True+ve /(True+ve + False-ve) Eye Department, Hvidovre Hospital, Denmark. Clinical diagnosis had been established by a neurologist in all cases. Erroneous diagnosis included a variety of other neurological disorders. 518 CDMS (Schumacher & Poser) Post-mortem 418 (94%) MS 33 (6%) not-ms 33 Probable MS (Poser) Post-mortem 22 (66%) MS 11 (33%) not-ms Engell T. Acta Neurol Scand Jul;78(1):39-44.
34 A clinico-pathoanatomical study of MS diagnosis SPECIFICITY = True-ve /(True-ve + False+ve)? 25% of cases of MS are undiagnosed in life (asymptomatic or benign cases) Multiple Sclerosis Engell T. Acta Neurol Scand May;79(5):
35 Case 5
36 What is the diagnosis?
37 What is the diagnosis?
38 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-beta-1b. See also 4. Possible side effects.
39 Who is Will Rogers?
40 Will Rogers Phenomenon in Multiple Sclerosis When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states.
41 Diagnostic criteria for Primary Progressive MS Polman et al. Ann Neurol 2005;58:840-6.
42 Accumulation of disability in PPMS: stratified by intrathecal IgG abnormalities 1.0 Proportion Progressing CSF Negative Positive P =0.03 Proportion Progressing as Percent Epoch CSF- CSF+ 6 mo mo mo mo Years to Progression Years Based on data from a second meeting of the DSMB and assume no therapeutic effect Slide courtesy of Jerry Wolinsky
43 PPMS diagnosed according the original McDonald criteria Not MS Not MS OCB-ve OCB+ PPMS Not MS OCB-ve PPMS OCB+ PPMS PPMS diagnosed according the New Polman-McDonald Criteria
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45 Will Rogers Phenomenon in Multiple Sclerosis Poser McDonald Sormani et al. Ann Neurol 2008;64:
46 MS diagnosed according the old Poser Criteria Inactive CIS Active CIS RRMS Inactive CIS Less active RRMS More Active RRMS MS diagnosed according the New McDonald Criteria
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48 Flags
49 My flags The 3 best investigation neurologists have are Repeating the history and examination Always step back and ask the question can it be something else? Flags Normal CSF: OCB-ve Abnormal CSF: raised protein, pleocytosis Systemic symptoms & signs; e.g. uveitis Age (>50) Ethnicity Comorbidities (vascular risk factors and headache) Neuropsychiatry (undoing the diagnosis) Peripheral nerve involvement Clinical Vigilance Clinical blindspots Go for the money Dual pathology (MND, CNS lymphoma, migraine, vascular disease)
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