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
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