Manuscript title: “Status of Diagnostic Approaches to AQP4-IgG Seronegative NMO and NMO/MS Overlap Syndromes”
Authors: M. Jurynczyk, B. Weinshenker, G. Akman-Demir et al. Journal of Neurology
Corresponding author: Jacqueline Palace, email address:
Patients with optico-spinal demyelinating diseases of the CNS – a request for expert opinion on the diagnosis and treatment.
Nuffield Department of Clinical Neurosciences
Oxford University Hospitals National Health Service Trust, Oxford, England
University of Oxford, Oxford, England
Abbreviations:
MP – methylprednisolone, IVMP – intravenous methylprednisolone
IVIG – intravenous immunoglobulins
OCB – oligoclonal bands
ON – optic neuritis
PEX – plasma exchange
TM – transverse myelitis
VA – visual acuity
Comments:
We give information on comorbidities and family history only when it is relevant.
Dates in bold letters indicate relapses or sustained disability progression.
All patients were tested for the presence of AQP4-Abs and were found to be negative.
Patients 2, 3, 5, 10, 11, 12 were tested for MOG antibodies and they were all found to be negative.
Extra information given on request:
Immunosuppressive regimes used: azathioprine 2.5 mg /kg or methotrexate 12.5-20 mg once weekly with prednisolone maintenance dose 5-15 mg once daily
Patient 11: Thymus histology benign, picked up on chest Xray, no myasthenia
Patient 12: MOG result given in response to question
Patient nr 1
Female, born 1971, Asian
2003: left ON (mild with full recovery)
Jan 2007: TM with sensory symptoms only (full recovery with oral MP)
MRI: short T7/T8 lesion with cord swelling and contrast enhancement
OCB negative
Feb 2009: TM with sensory symptoms (full recovery after 6 months with MP, oral and then i.v.).
Spine MRI: short C2/3 lesion with contrast enhancement
Brain MRI: normal
VEP delayed in the left eye (114 ms)
Immunosuppression started in Jun 2009
An axial image from the MRI performed at the acute phase of the relapse in Feb 2009.
Feb 2011: Paresthesias in both arms
MRI: residual C2/3 lesion
Brain MRI: minor nonspecific periventricular white matter hyperintensities
MRI shown below was performed in May 2011, 3 months after the patient complained of pins and needles in both arms. I paste the C2/3 lesion axial image and a scan from below the lesion to compare. Probably the lesion is residual from the previous attack.
MRI in Mar 2012 – unchanged from previous
Aug 2013 – the patient is stable, EDMUS 1.0. Vision normal.
Patient nr 2
Female, born 1967, Caucasian
2001: sensory symptoms in limbs and trunk lasting 6 months
2002: sensory symptoms and weakness in limbs
Spine MRI (Oct 2003): short lesions at C4 and T9,
Brain MRI normal
Nov 2003: numbness in right leg and trunk to T6 (IVMP)
OCB positive
Brain MRI normal
Immunosuppression started in May 2004
May 2007: Ascending paresthesias to C7
Spine MRI: short lesions at C3/4 and C5/6
Mar 2008: weakness of lower limbs and Lhermitte sign (improvement with oral MP). EDMUS 5.0
Oct 2011: weakness and numbness in both arms
Spine MRI: unchanged from previous
Brain MRI: Two T2 hyperintense lesions, one juxtacortical (R, anterior, frontal) below and one in left corona radiata
VEP normal
Feb 2013: EDMUS 5.0, frequent urinary tract infections on immunosuppression
Over the last 5 years there was no significant disability progression in this patient. She was able to walk < 500 m without rest in 2008 and the walking distance remained approximately the same since then.
Patient nr 3
Male, born 1990, Caucasian
Jan 2011: Ataxia, vertigo, diplopia, vomiting and right-sided weakness. Symptoms progressed over 1 week.
Brain MRI without contrast: brainstem lesion in the right middle and inferior cerebellar peduncles and medulla extending to upper cervical cord, periventricular and juxtacortical lesions
Initial improvement with IVMP, but 2 weeks later severe transverse myelitis with paraplegia, urine and faecal incontinence and sensory level at T8, and right optic neuritis
Spine MRI: Lesion extending from brainstem to C1/2, 2.5 segment lesion at C5-7, short
lesion at T6/7, all lesions enhance with gadolinum
Brain MRI with contrast: enhancement of lesions
The patient underwent PEX and could walk prior to discharge.
CSF acellular, OCB absent
Discharged on tapering steroid dose.
Feb 2011: Transverse myelitis with paraplegia. IVMP and PEX with good recovery. EDMUS 8.0 → 6.0. Immunosuppression started.
MRI: a new lesion at T2/3
Jan 2012: Sensory disturbance on the left side of the face and on left arm (IVMP)
Brain MRI: new lesion in the midbrain on the right side and pre-central juxtacortical lesion showing Gd enhancement
Immunosuppression stopped due to pancytopenia.
Feb 2013: urinary retention, back pain and reduced mobility (IVMP)
May 2013: acute painful urinary retention (IVMP)
Spine MRI: new small lesion T6/7, old lesions almost entirely resolved
Brain MRI: no new lesions in the brain, partial resolution of old lesions
Nov 2013: The patient is stable. EDMUS 6.0.
Patient nr 4
Male, born 1973, Caucasian
March 2005: left ON (0.2 at worst, good recovery over 2 weeks without treatment)
Apr 2006: left ON (complete blindness, spontaneous improvement)
Brain MRI: high signal in left optic nerve, otherwise normal
Jan 2008: right ON (complete blindness, prompt recovery with oral MP)
June 2008: TM with left hemisensory disturbance (oral MP with improvement)
Jan 2009: right ON (slight darkening of vision, recovered without treatment)
June 2009: mild right ON
Apr 2013: mild right ON (oral MP, good recovery)
Vision: normal in both eyes
VEP normal
Spine MRI: short lesion at C5
Brain MRI normal
In 2008 only brain MRI was done, which was normal. Spine MRI was performed in Mar 2010 when the patient was referred to our NMO Clinic. It showed a short lesion at C5. Please find it below.
OCB were not detected in the CSF. Pleocytosis normal, protein 0.79.
Patient nr 5
Female, born 1950, Caucasian
2000: right optic neuritis (excellent recovery without treatment)
Feb 2009: paresthesia in the right hand, dysesthesia in the left leg, deafness in the right ear, disequilibrium (almost complete recovery with oral prednisolone over several days, EDMUS 5.0 → 2.0)
Aug 2009: burning discomfort in both legs and right arm, weakness of the right arm (improved with oral prednisolone, EDMUS 3.0 → 2.0)
Nov 2009: upper limb weakness, urinary hesitancy requiring intermittent self-catheterisation (EDMUS 6.0)
PEX in March 2010 (EDMUS 5.0)
Spine MRI: T2 hyperintensity C3 to C6
Brain MRI: lesions in the floor of 4th ventricle, few subcortical lesions and one periventricular lesion
Immunosuppression started.
Oct 2010: Burning pain in both thighs and right forearm, weakness in the left arm (IVMP with some improvement). EDMUS 5.0.
MRI: no new lesions
CSF: acellular, OCB present
VEP: marked delay in the right eye
Aug 2012: increasing weakness in the right leg (oral MP with good response, EDMUS 7.0 → 6.0)
Patient nr 6
Female, born 1955, Black British
Oct 2013: Shingles in the right arm and then progressive numbness, weakness and pain in right arm over 4-6 wks (EDMUS 5.0)
Spine MRI: LETM on right side of the cord from cervicomedullary junction to C4 with swelling
Brain MRI: non-specific brain lesions
CSF: acellular, normal protein, OCB negative, PCR HSV negative
PCR for Herpes varicella/zoster virus was done at the acute phase and was found to be negative.
Patient nr 7
Male, born 1978, Caucasian
Family history: mother – MS and type 1 DM, half-sister – MS
Family history details: patient’s mother developed MS in her mid 30s and is now 69 years old and bed-bound and very disabled. She has been affected with mobility problems, bladder dysfunction, sensory abnormalities in the limbs, severe tremor and visual problems. She is the daughter of a Native American Indian (Najavo). She also has diabetes, rheumatoid artritis and alopecia. Patient’s sister has the same mother as him but a different father and developed ‘MS’ in her 30s and is now 40. The patient is not in regular contact with her.
Oct 2010: severe right ON (hand movement, recovery without treatment over 9 months to VA 0.9)
July 2011: moderate right ON (recovery without treatment to VA 0.9)
July 2012: TM with bilateral hand paresthesias and band-like sensation T8-10 (recovery without treatment, EDMUS 2.0 → 1.0)
CSF: acellular, normal protein, OCB present
VEP delayed in the right eye
Spine MRI: LETM C1 to C5 and T7 to T11, mainly central or holocord, some slight cord swelling
Brain MRI: small T2 hyperintensities adjacent to corpus callosum and in white matter of both cerebral hemispheres
Oligoclonal bands were detected in the CSF alone.
Patient nr 8
Female, born 1984, Caucasian
March 2012: TM with weakness and sensory disturbance in the lower limbs
July 2012: left ON with blurred vision and retro-orbital pain.VEP: delayed latency in the left eye
Spine MRI: LETM throughout most of cord with swelling and patchy enhancement
Brain MRI: few non-specific lesions
Jan 2013: IVMP with resolution of symptoms (but still has spasticity and clonus on examination, EDMUS 5.0, vision normal in both eyes)
Feb 2013: for several weeks reports increasing stiffness in legs and impaired walking (oral prednisolone with improvement)
Brain MRI: few periventricular and subcortical lesions
CSF was done in Feb 2013 and showed: WBC 18, OCB present, protein normal, CSF AQP4-Abs negative.
Systemic vasculitic screen – negative.
Patient nr 9
Female, born 1956, Caucasian
Dec 2004: mild left ON
Jan 2005: severe right ON (to counting fingers, no recovery)
Oct 2005: mild left ON
Severe right optic neuritis, which occurred in Jan 2005 had rapid onset. The loss of vision in the left eye in Oct 2005 was more gradual. VEP was performed just before the onset of her left visual problems and showed a delayed response on the left with absent response on the right. Since then the vision was gradually deteriorating without any distinct attacks. Response to steroids was not convincing. No optic nerve enhancement was found in the MRI at any stage. LHON mutations were negative.
Both discs pale.
VEP: absent in the right eye, delayed in the left eye
OCB present in the CSF
Apr 2006: left ON (to 0.2, improvement with steroids to 1.0 over 3 months)
Oral steroids started and after several dose adjustments continued until now
Feb 2009: immunosuppression started
Mar 2011: reports gradual deterioration of VA in the left eye (0.7), urinary urgency and occasional faecal incontinence
Brain MRI normal
Spine MRI small lateral lesion C3/4
Mar 2013: deterioration of visual function in the left eye (VA: L 0.5, R 0.1)
Brain MRI: non-specific deep white matter hyperintensities
Spine MRI small lateral lesion C3/4 (old)
Jan 2014: deterioration of visual acuity in the right eye (VA L 0.7, R counting fingers)
Patient nr 10
Female, born 1983, Caucasian.
July 1994: severe left ON (to no light perception with limited recovery)
CSF acellular, OCB negative
Brain MRI: high signal left optic nerve, otherwise normal
July 1996: severe right ON (VA 0.1, good recovery with oral prednisolone to 0.5)
LHON negative
Brain MRI normal
Nov 1996: severe right ON (VA 0.1, long-term oral prednisolone started, recovery to 0.3)
May 1997: right ON (immunosuppression started)
2005: prednisolone stopped
Spine and brain MRI normal
Nov 2011: bilateral ON (IVMP, light perception in the right eye, no light perception in the left eye)
Prednisolone added to immunosuppression.
LHON mutations were negative.
Patient nr 11
Male, born 1956, Caucasian
Comorbidities: thymectomy for thymoma
Oct 2006: bilateral ON (IVMP with good response)
ANA and dsDNA positive
MRI: high signal in the floor of third ventricle
CSF: 10 cells, OCB absent
Oct 2009: TM with lower limb weakness and sphincter involvement (IVMP with excellent improvement)
VEP delayed in both eyes
MRI: LETM C3-C6
2010: thymectomy for thymoma
June 2010: TM with lower limb weakness (IVMP with good recovery)
Oct 2010: TM with lower limb weakness (IVMP with good recovery)
2012: no new symptoms
Brain MRI: diffuse signal change around splenium with mass effect
Spine MRI: complete resolution of cervical cord lesion
Immunosuppression started.
Jan 2014: the patient is stable
Patient nr 12
AM, female, born 1988, Caucasian
Sep 2013: Constipation and headache and then after 2 weeks vomiting, visual disturbance, leg paraesthesia and left arm weakness
Progressed to complete blindness in both eyes (no light perception), paraplegia, T5 sensory level and urinary retention (IVMP with no improvement, IVIG complicated with aseptic meningitis, PEX)
Spine MRI: LETMS C6 to T1 and T4 to T6
Brain MRI: multiple T2 high signal lesions with enhancement
CSF data: pleocytosis 58 (all lymphocytes), protein 0.62, OCB – not available.
ANA normal.
Vision improved over months to 0.25 bilaterally
Follow-up: no further relapses
Patient wheelchair-dependent (EDMUS 8.0), intermittent self-catheterisation once daily, VA 0.1 bilaterally
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