MS Masterclass 6.2 17 May 2019 Case Presentations Dr John Thorpe - - PowerPoint PPT Presentation

MS Masterclass 6.2 17 May 2019

Case Presentations Dr John Thorpe

Case 1

History

• 37 year old agricultural machine worker
• First seen April 2016

– Diplopia (with INO to left) – Dysarthria – Dysphagia – Left sided weakness and ataxia

History

• Previous episode 2013

– Pins and needles left hand – Clumsy – Recovered in two weeks – Attributed at the time to “frozen shoulder”

• MRI

History

• Treated with methylprednisolone
• “85% better”
• Few weeks later

– Altered sensation to buttocks – Bladder disturbance – Affected walking

Management

Management

www.engage.england.nhs.uk/consultation/specialised-services- algorithm/user_uploads/treatment-algorithm-with-notes-v9.pdf

McDonald criteria (2017)

Lancet Neurol 2018; 17: 162–73

Management

www.engage.england.nhs.uk/consultation/specialised-services- algorithm/user_uploads/treatment-algorithm-with-notes-v9.pdf

Management

• First line DMTs

– 2 attacks in 2 years

• Natalizumab

– 2 attacks in 1 year

• Both disabling
• Alemtuzumab

– Brainstem onset in middle aged male – 2 attacks in quick succession – Residual disability

Variations in prescribing

Current patients on DMTs in Cambridge

• Interferon

90

• Glatiramer

71

• DMF

202

• Teriflunomide

1

• Fingolimod

129

• Alemtuzumab

245

• Natalizumab

54

• Ocrelizumab

12

• Cladribine

22

• TOTAL

826

Current DMTs

50 100 150 200 250 300 Apr-13 Jun-13 Aug-13 Oct-13 Dec-13 Feb-14 Apr-14 Jun-14 Aug-14 Oct-14 Dec-14 Feb-15 Apr-15 Jun-15 Aug-15 Oct-15 Dec-15 Feb-16 Apr-16 Jun-16 Aug-16 Oct-16 Dec-16 Feb-17 Apr-17 Jun-17 Aug-17 Oct-17 Dec-17 Feb-18 Apr-18 Jun-18 Aug-18 Oct-18 Dec-18 Feb-19 Apr-19 Tecfidera Series2 Series3 Tecfidera Alemtuzumab Series11 Series4 Series5 Series6

Alemtuzumab DMF Fingolimod Interferon Glatiramer Natalizumab Cladribine Ocrelizumab

Clinic Growth

100 200 300 400 500 600 700 800 900 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 Start stop Total

EMA April 2019

EMA Evaluation

• 25,000 patients treated
• 7 Cerebral haemorrhages
• 4 Pulmonary haemorrhages
• During or soon after infusion

– Especially first

• Raised BP

EMA evaluation

EMA Evaluation

• Lemtrada only for highly active MS despite two DMTs
• Also

– Autoimmune hepatitis – Haemophagocytic lymphohistiocytosis – Neutropaenia – Arterial dissection – Stroke and MI

Case 1 Management

• June 2016

– First cycle Alemtuzumab – Three days IVMP 1g/day – Prophylactic Acyclovir and Cotrimoxazole

Progress

• 20 April 2017

– 12/7 headache – 8/7 diplopia – 5/7 confusion – Progressive unsteadiness and falls – Admitted to local DGH and transferred to Addenbrookes

Examination

• Confused
• Not orientated TPP
• Knew DOB but not age
• ?L homonymous hemianopia
• Dysconjugate gaze
• Tortional Nystagmus
• ?Right VI and L VII palsy
• Weak legs
• Extensor plantars

Management

Bloods and CSF

• FBC (lymph 0.8), U+E, LFTs, CRP, ESR, TFTs, Vit B12
• ANA, ANCA, HIV, Hep B+C, syphilis, streptococcal and atypical resp

serology, VZV/HSV serology, toxoplasma, Cryptococcus, Borrelia

• Negative Ganglioside, NMO and MOG abs
• CSF – protein 0.85, WCC 200 (lymph 90%,poly 10%), RBC 68, gluc

3.7 (no serum), gram stain negative, Adeno/HSV/VZV/EBV/VDRL/HHV6/JC/BK negative, Cryptococcus negative, AFB not seen, TB culture negative, OCBs + (serum-), cytology – reactive lymphocytes

MRI

MRI

April 2017 April 2016

MRI

April 2017 April 2016

MRI

April 2017 May 2017

Progress

• Aciclovir, ceftriaxone, amoxicillin
• IV methylprednisolone
• Deteriorated

6 days post admission

• Not verbalising or following commands
• R ptosis
• Almost complete ophthalmoplegia, pupils reactive
• Severe tetraparesis

– Able to move right arm only (localising to pain)

• Intubated

MRI

April 2017 May 2017

MRI

April 2017 May 2017

Further Treatment

• 10 cycles plasma exchange

– No immediate response

• Continued on oral steroids

– Prednisolone 60mg/d

• 3 cycles of cyclophosphamide
• 2 cycles of Rituximab

Progress

• 23 May

– Some movements of eyes

• 31 May

– Able to communicate with eyes and communication board

• 6 June

– Voluntary movement of right arm – Emotional lability

Progress

• 13 June

– Able to grip with right hand

• 15 June

– Speaking valve

• 22 June

– Extubated – 2/5 power arms R>L

Progress

• 6 July

– Sitting out, catheter removed – Able to reach nose with right hand

• 21 July

– 3/5-4/5 power in legs

• Transferred to rehab

– Discharged 25 Sept 2017 – Taking a few steps with a frame

Alemtuzumab

• Anti-CD52 antibody
• Reduces relapse rate by 49-55% cf Rebif
• 70-80% reduction cf placebo
• Reduces accumulation of disability
• Thyroid disease 1 in 3
• ITP 1-2%
• Renal failure >1:1000
• EMA currently re-evaluating

– cerebral and pulmonary haemorrhage

Diagnosis

• Presumed severely exacerbated CNS inflammation after

Alemtuzumab

• Haghikia et al. Lancet neurology Feb 2017

– Two patients (41 year old M, 25 year old F) – Severe exacerbation 5 and 9 months after Alemtuzumab – Unresponsive to steroids – Improved following PLEX and Rituximab

MRI

Haghikia et al. Lancet neurology Feb 2017

B-cell driven?

• B cells repopulate 3-6 months

– Naïve bone marrow derived

• T cells

– CD4 35 months – CD8 20 months

• Timing in keeping with other B cell driven autoimmunity
• Response to PLEX and Rituximab

Targeted Depletion

Neutrophils Monocytes Eosinophils Basophils Neutrophils Monocytes Eosinophils Basophils Results(109/L) Months

Slide courtesy of Dr Jo Jones

Depleted cells recover at varying rates

B cells T cells

Slide courtesy of Dr Jo Jones

Naive B cells dominate

% memory B cells

M0 M1 M3 M6 M9 M12 M13 M15 M18 M21 M24 M25 M27 M30

MONTH OF TREATMENT

0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0

% OF B CELLS THAT ARE MEMORY

** ** **

Pre 1 3 6 9 12 13 15 18 21 24 25 27 30

70 60 50 40 30 20 10

Alemtuzumab Alemtuzumab Alemtuzumab

Slide courtesy of Dr Jo Jones

Progress

• Continued ongoing improvement
• Continuing on Rituximab
• June 2018

– Walking with a stick approx 100m – Hoping to get back to work – Ataxic gait, normal eye movements, minimal weakness.

MRI

April 2017 May 2017 Sept 2018

MRI

April 2017 May 2017 Sept 2018

Case 2

History

• 52 year old F
• Reviewed Aug 2018 in DMT clinic

– Wants Alemtuzumab

History

• Childhood squint
• Corrected with exercises
• Hammer toes
• Surgery aged 9 (little toes amputated)
• Tripping over right foot since ~21

– ?woke up with this – Never resolved – Spasms of foot, with flexion of toes – Partial response to Pregabalin

• Fluctuating problems with hearing
• MRI 2003 Nothing abnormal found

History Continued

• ~2010

– Urinary frequency and hesitancy – Reduced awareness of bowels – Swallowing problems

• Endoscopy and then fundoplication
• Spontaneous bowel perforation requiring temporary stoma
• Ongoing problems with bowels since (esp constipation)

History Continued

• 2012

– Reduced vision in both eyes over weeks – Cataracts and corneal dystrophy

• (Map dot fingerprint corneal dystrophy)

– Cataract surgery (2015)

• Intermittent diplopia since, esp looking into the distance
• 2016 onwards

– “Excruciating” pain in feet – Right foot numb and tingly. Period on holiday when could not keep flip flops on

History Continued

• 2016

– Vertigo – Persisted for ~two months – Further episodes since (including two in 2018)

• April 2017

– Reduced vision in left eye for 24 hours with pain

History Continued

• June 2017

– Numbness of right ulnar fingers. Sudden onset, persisted for three weeks, recurred in December and persisted

• Summer 2017

– Awoke with numb right face, persisted for six weeks – Ongoing intermittent tingling of lips and chin

History Continued

• Feb 2018

– Tight pain in head – GP treated with steroids – Diplopia resolved – Lost interest in things – Problems with concentration and memory

History Continued

• PMH

– Migraine – Depression – Hypothyroidism – Strong FH of glaucoma - Prophylactic iridotomies

History Continued

• FH

– Daughter renal failure

• On transplant list
• Reviewed by genetics ?diagnosis

– Father diagnosed PD

• PH

– Non smoker – Little EtOH

Examination

• ?slightly dysarthric
• Acuity reduced in (amblyopic) L eye
• Normal colour vision and fundi
• Mild difficulty tandem walking and hopping
• Mild weakness of right hip flexion and ankle dorsiflexion
• Moderately brisk reflexes
• Equivocal plantars
• Reduced pinprick sensation in right foot and ulnar three

fingers of right hand

Summary

• 52 year old woman
• Recurrent (abrupt) neurological episodes since 20s
• Corneal dystrophy, cataracts, bowel perforation, +/-

deafness

• Possible FH of renal disease
• Relatively minor signs on examination
• Should she have Lemtrada?

Investigations

– Routine haematology and biochem normal – MRI – CSF

• Normal. Negative OCBs

MRI

MRI

What Now?

– Slightly indignant email

• Already seen several neurologists
• Wants Alemtuzumab ++

Does she have MS?

– Susac’s

• Normal angio
• ?Relevance of corneal dystrophy

– ?Vascular

• Fabry’s

Investigations

– Repeat MRI

• unchanged

– Repeat CSF

• Normal again. Negative OCBs

Investigations

– ESR normal – Thrombophilia screen normal – Complement N – ACE N – White cell enzymes normal – ANA/ANCA Neg – Alpha-galactosidase normal

Investigations

– GEMINI panel – Heterozygous likely pathological variant in COL3A1

• Procollagen III
• Type III collagen

– Vascular Ehlers-Danlos syndrome (IV)

Vascular Ehlers-Danlos Syndrome

– Variable hypermobility, skin fragility – Predominantly large vessel disease

• Vascular rupture/dissection
• Also intestinal rupture
• Uterine rupture

– Valvular prolapse – Spontaneous pneumothorax – No definite association with MS – ?Corneal dystrophy

Small fibre neuropathy

Cazzato et al

Progress

• Still being managed as OCB neg MS
• Started on Tecfidera but did not tolerate

– (worsening abdominal pain and diarrhoea)

• Reviewed

– No problems with wound healing or dislocations – Renal history in daughter still not clear – No other FH

Progress

• No hypermobility
• Easily palpable aorta

– (CTA normal)

• Various scars
• Referred to genetics

Genetic Review

• Mutation highly likely to be pathogenic

– Null mutation in COL3A1 – History of dislocated shoulder, easy bruising, varicose veins from teens and joint pains

Genetic Review

– O/E

• “Facial Gestalt of EDS IV”
• Acrogeria
• Translucent skin on chest and arms
• Smooth skin with striae
• Varicose veins
• No hypermobility

Progress

• Awaiting cardiology review
• Also undergoing further GI investigations
• Not currently on DMT

Case 3

• 42 year old M
• Previously fit and active

– Boxed aged 8 to 18 – Almost made it to Olympic team

History

• 42 year old M
• Previously fit and active

– Boxed aged 8 to 18 – Almost made it to Olympic team – Longstanding mental health problems

• Anxiety
• Depression
• Agoraphobia : housebound for years

History

• Moved house in August 2017

– Partner’s children going to school locally

• “Acute stress reaction”

– Appeared to be in a trance – Disorientated – Unable to follow instructions – Confused with poor memory

History

• Ongoing problems

– Just sitting in front of TV – Staring into the distance – Unable to follow simple commands – Needing prompting to eat and drink – Sending odd texts to his parents “just random letters” – Poor spatial awareness

• Walking into door frames

– CT …

CT

History

• October 2017

– Possibly some improvement in cognition – Abrupt onset of walking mobility – Shaking of right arm and leg – Unsteady – Had to start sleeping downstairs

• December 2017

– Wheelchair bound – Only able to take a couple of steps – Incontinent

History

• PMH

– Longstanding psychiatric problems

• 1991 “Phobic anxiety disorder”

– No previous neurological symptoms

• Meds

– Citalopram 40mg, Diazepam 2mg tds, Propranolol 40mg prn,Omeprazole 20mg od

• Smokes. No EtOH (previously heavy)

– Previous illicit drugs esp cocaine

• No FH

Examination

• Broken pursuit
• Discs normal
• ?Tic
• Increased jaw jerk
• Increased tone in all four limbs
• Brisk reflexes, clonus, ext plantars

History/Examination cont

• December 2017

– Further deterioration – Unable to stand

• Examination

– Very anxious and agitated – Wearing dark glasses – Not orientated in time or place – Mild incoordination – Moderate pyramidal weakness of legs

Summary

• 42 year old man
• Former boxer
• Long psychiatric history
• 5 month history of cognitive symptoms
• 3 month history of mobility problems and incontinence
• Abnormal CT scan

Investigations

• CT diffuse white matter low attenuation
• FBC, Biochem, ESR Normal (low phosphate), normal

electrophoresis

• Complement normal
• Lactate normal
• ANA, ANCA, Anticardiolipin Neg
• HIV neg

Investigations

• MRI
• CSF

– WCC 42 (90%) lymphs – Protein 0.95 g/L – Glucose 3.2/5.0 – Locally synthesised OCBs

Balo Concentric Sclerosis

• Balo J. Leucoencephalitis periaxialis concentrica. Magy Orvosi Arch

1927;28:108-24

• (Marburg 1906)
• Acute CNS disorder with concentric rings of demyelination alternating with

relatively myelinated tissues

• Initially pathological (PM) diagnosis
• Similar appearances on MRI
• ?Just severe acute MS

– ~half of cases in literature in context of MS – Not all develop MS – OCBs often absent

Balo concentric sclerosis

Balo Concentric Sclerosis

• F 55%
• Mean age of onset 34
• Presentation

– Progressive encephalopathy – Fever – Behavioral changes – Cognitive deficits – Headache, seizures – Increased intracranial pressure – Focal neurologic deficits – Stroke like presentation described – Rare asymptomatic MRI changes

Balo Concentric Sclerosis

• Course

– Subacute, progressive, fatal – Prognosis often <1 year – Monophasic, relapsing, progressive

• Treatment ??

– Acute

• Steroids
• Immunosuppressants
• Plasmaphoresis
• IVIG

Balo Concentric Sclerosis

• Treatment ??

– Chronic

• MS DMTs
• Azathioprine
• Mitoxantrone
• Cyclophosphamide
• ?Natalizumab
• Alemtuzumab ineffective (n=1)

– Brown, Coles, Jones Mult Scler 2013

• Prognosis

– Initially PM diagnosis…

• 14% dead or severely disabled in a year
• 3% ?Devic
• 19% MS like course
• 26% stable >2 years
• 38% stable FU < 2 years

Balo Concentric Sclerosis

• Mechanism

– ?NO and oxygen free radicals inhibiting COX-1 – Induced protective HIF-1 alpha and HSP-70 in adjacent oligodendrocytes – Other clever mathematical models based in non-linear chemotaxis…

Progress

• IVMP 1g x 3 days
• Commenced on Pred 60mg
• Temporary improvement for a few days
• Unable to walk again
• Doubly incontinent
• Plan for PLEx
• IVIG

– No improvement

Progress

• IVMP 1g x 3 days
• Commenced on Pred 60mg
• Temporary improvement for a few days
• Unable to walk again
• Doubly incontinent
• Plan for PLEx
• IVIG

– No initial improvement

Progress

• Oct 2018
• Gradual improvement over months
• Mostly continent
• Transferring from bed to commode/wheelchair
• Cognitive issues ?functional component

– Had further psychiatric review

Examination

• Not orientated in place or time
• Tone increased in legs with extensor spasms
• Normal power
• DNAd repeat MRI

Case 4

History

• 23 year old M
• 1/1/11 Woke during night

– Felt sick and breathless – Gasping for breath – Tingling left side

• Ambulance called

– Headache, vomiting on way to A&E

• Taken to Resus

– Sweaty, unwell – Collapsed

Progress/Investigations

• AF then VT

– 1x 150 J DC shock – Ventricular bigeminy

• Routine bloods normal
• Corrected Ca 1.67mmol/l (Albumin 57 ??)
• Glucose 14.1mmol/l
• Trop T <3ng/l

– Repeat post shock 752

• Paracetamol/Salicylate neg
• CT normal (large cisterna magna)

ECG

ECG post shock

ECG

ECG

Progress

• Echocardiogram

– LV function moderately impaired – Ejection fraction 35% – Mid to basal walls stiff and hypokinetic

• Further VT on ward (terminated spontaneously)

Progress

• Transferred urgently to Papworth

– Cardiac MRI

• Improved LV function
• No delayed enhancement

– Angio normal – Normal electrophysiological study – ?Coronary artery embolus – ?Spasm – Dual antiplatelet therapy – Betablocker – Subsequent outpatient TOE

Neurological History

• Whilst in Papworth

– Speech slightly slurred – Repeat CT unchanged

• After discharge

– Worse – Increased tingling left arm and face – Right leg felt weak – Consulted GP – Improved spontaneously

Presented again

• 1/2/11

– Acute deterioration – Awoke during night with headache, nausea and vomiting – Slurred speech – Diplopia – Had to crawl down stairs – Admitted to PCH

Examination

• (7/2, JWT)

– Sinus rhythm – Haemodynamically stable – Cerebellar dysarthria (mild) – Hypometric saccades to left – Very broken pursuit eye movement – (no ophthalmoplegia) – Reduced light touch left lower face – Normal power/reflexes/sensation – Markedly impaired coordination L arm>leg

Past History

• Healthy
• No EtOH, smoking, drugs
• No medication normally
• No family history of sudden cardiac death/ischaemic heart

disease

Summary

• Previously fit 23 year old man
• Acute cardiac rhythm disturbance
• Initial neurological symptoms which got worse over a

week or two then improved

• Acute deterioration

– Ataxic – Dysarthric – Sensory signs in left face

Discussion

Discussion

– Primary cardiac problem with emboli – Drugs – Myocarditis and ADEM – ?Sarcoidosis – None of the above

Investigations

• Routine haematology, biochemistry Normal
• Prothrombotic screen normal
• ANA, ANCA neg
• ECG
• MRI

MRI

MRI

ECG 1/2/11

Lumbar Puncture

• Protein 0.61g/l
• Glucose ?
• WBC 32 /µl (Lymph 80%, Poly 20%)
• OCBs positive, weakly positive in serum

Progress

• ECG returned to normal
• Reviewed by JWT 14/3
• Improved spontaneously during admission and after

discharge

• Slightly off balance
• Speech and vision normal
• Sensation normal

Progress

• But…
• 3 weeks after discharge
• Pain in back radiating to anterior abdomen
• Weakness of left leg

Examination

• Ataxic gait
• Eye movements normal
• Very mild left FN ataxia
• Weak left hip flexion > right
• Reflexes not brisk. Plantars downgoing
• Sensory level to pain and temp to T9 on L
• Dysaesthetic band T11 R
• Impaired proprioception L (sic) toes
• Repeat MRI. Brain lesions smaller.

MRI

Stress and the heart…

“Voodoo death” and its friends

• MA Samuels. Cleveland Clinic Medical Journal (2007) 74 suppl 1

S8-S16

– Walter Bradford Cannon 1942

• “Voodoo death”
• Extreme emotion, lack of external control
• “sympathico-adrenal system”

– Experimental evidence of autonomic storm

• Sympathetic and parasympathetic
• Neurally mediated >> adrenal

– ECG changes Large/inverted T waves, prolonged QT, changes of acute anterolateral infarction, repolarisation changes and dysrhythmias

Progress

“Voodoo death” and its friends

• Pathology

– Subendocardial – Myocardial stunning – Calcium influx, failure of calcium channel closure – Myocytes die in state of contraction (cf typical MI) – “contraction band necrosis”

Takotsubo cardiomyopathy

• Sato et al 1990
• Tako-Tsubo

– Japanese octopus trap

• Post menopausal women
• Stress
• Predominantly apical
• Raised catecholamines
• Contraction band necrosis

“Inverted” Takotsubo

• Base affected
• Apex contracts normally

Neurology and the heart

• Central control of BP/heart rhythm
• Insula

– R symp, L parasymp

• Anterior cingulate, amygdala
• ?Orbitofrontal cortex
• Hypothalamus

Neurological Associations

• Intracerebral haemorrhage

– Especially subarachnoid

• Stroke
• Phaeochromocytoma
• SUDEP
• Guillain Barre
• Acute Multiple sclerosis

– Heart, Lung and Circulation (2009) 18, 155-158

• J. Makaryus, S. Kapphahn, A. Makaryus

Further reports…

• Webb et al. Neurology 2014

– Medullary lesion

• Biesbroek et al. Int J Cardiol 2016

– Acute first presentation with frontal lesion

• Midaglia et al. MSJ 2016

– First presentation, lesions above and below tentorium

• London et al. Acta Neurol Belg 2018

– First diagnosis, presenting with ataxia

• Prestipino et al. MSARD 2018

– Brainstem relapse

• Bayer et al. MSARD 2019

– 2 cases with medullary lesions

Diagnosis

• Acute multiple sclerosis presenting with (Inverted)

Takotsubo cardiomyopathy

• ?

Subsequent Progress

• Typical MS course
• Multiple DMTs

– Including Fingolimod – No further cardiac problems

• Currently just had Cladribine