Published diagnostic criteria or consensus opinions were utilized when available to establish specific CIDOMS diagnoses (neuromyelitis optica1, stiff person syndrome2, primary cerebral vasculitis3, neurosarcoidosis4, neuro-Behcet’s5, radiologically isolated syndrome6, chronic relapsing inflammatory optic neuropathy7 and acute disseminated encephalomyelitis8.

Table e-1Diagnosed cases

DIAGNOSIS / CLINICAL PICTURE / BASIS ON WHICH DIAGNOSIS WAS MADE
ADEM / encephalitis with multifocal features (headache, seizures, left-sided pyramidal weakness, confusion) / acute florid onset; typical MRI features with extensive white matter change & right hemispheric swelling; negative oligoclonal bands
ADEM / encephalitis with multifocal features (headache, left-sided pyramidal weakness) / acute florid onset, influenza vaccine 1 month previously; typical MRI features with extensive white matter change & right hemispheric swelling, negative oligoclonal bands
ADEM / encephalitis with multifocal features (headache, confusion, right-sided pyramidal weakness) / acute florid onset, flu-like illness 10 days prior, typical MRI features with extensive white matter change; negative oligoclonal bands
Anti-Hu syndrome / sensory ataxic neuropathy, dysautonomia, bulbar symptoms / positive anti-Hu antibodies with central involvement (CSF Type II oligoclonal bands, raised IgG index)
Atypical MS / episodes of headache with different neurological symptoms (including inferior homonymous quadrantanopia, limb weakness, oscillopsia, left facial numbness, nausea, imbalance) / white matter lesions with distribution and orientation reminiscent of multiple sclerosis but no radiological evolution with followup despite varying clinical picture; negative oligoclonal bands; atypical clinical history with headache prominence; in view of this, definite diagnosis of MS not established; extensive investigation for alternative inflammatory / infectious diagnoses and CADASIL negative
Atypical MS / right optic neuritis, Lhermitte’s symptom, altered sensation over trunk, pins and needles over face & left arm, vitritis, recurrent diarrhoea / high signal in right optic nerve & white matter lesion in cervical cord on MRI; CSF Type II oligoclonal bands; persistent CSF pleocytosis (48-77 mononuclears / mm3); definite diagnosis of MS not established in view of marked systemic features and atypically persistent high CSF lymphocytosis; extensive investigation for alternative inflammatory / infectious diagnoses negative
Cerebral vasculitis (presumed) / multiple transient episodes of left-sided weakness & slurred speech, homonymous hemianopia, eventual permanent left-sided weakness & spasticity / multiple stenoses in various arterial territories on catheter angiogram with evolution on sequential CT angiograms, and corresponding infarcts; high CRP = 250mg/L; CSF pleocytosis (40 mononuclears and 3 polymorphs / mm3); elevated IgG index; brain biopsy declined; extensive investigation for alternative inflammatory / infectious diagnoses negative, good response to steroids & cyclophosphamide followed by methotrexate
Cerebral vasculitis (presumed) / encephalopathy / rheumatoid arthritis; white matter lesions; patchy perfusion defects on HMPAO SPECT in various arterial territories; lymphocytic pleocytosis (13/mm3); CSF Type II oligoclonal bands; extensive investigation for alternative inflammatory / infectious diagnoses negative; good response to steroids hence biopsy not performed
Cerebral vasculitis / headache, encephalopathy / primary lymphocytic & granulomatous angiitis on brain biopsy; extensive investigation for alternative inflammatory / infectious diagnoses negative
Cerebral vasculitis / ataxia, encephalopathy, left hand weakness / primary lymphocytic angiitis on brain biopsy; extensive investigation for alternative inflammatory / infectious diagnoses negative
Chronic relapsing inflammatory optic neuropathy / relapsing bilateral optic neuropathy / rapid and good response to steroids; negative anti-aquaporin 4 antibodies; negative oligoclonal bands
Lymphocytic hypophysitis + clinically isolated syndrome / headache, bitemporal hemianopia, diplopia, paraesthesiae, right optic neuritis / hypophysitis on pituitary biopsy; positive anti-pituitary antibodies; delayed visual evoked potentials
Paraneoplastic phenomenaof lymphoma (presumed) / sensorimotor peripheral neuropathy, bulbar symptoms / extensive enhancing white matter lesions & demyelinating neuropathy; lymphoma eventually diagnosed on mediastinal lymph node biopsy; still unsure whether CNS involvement was direct lymphomatous infiltration or paraneoplastic process (deceased, no post-mortem)
Paraneoplastic phenomenaof lymphoma (presumed) / transverse myelitis / no lymphomatous infiltration of CNS on post mortem histology
Neuro-Behcet’s disease / meningoencephalitis / scrotal ulceration; neutrophilic pleocytosis
Neuro-Behcet's disease / meningitis / orogenital ulceration; uveitis, arthralgia
Neurosarcoidosis (definite) / hydrocephalus, ataxia, vertigo, diabetes insipidus & radiculopathies / leptomeningeal biopsy
Neurosarcoidosis (definite) / gait problems, hydrocephalus, dysphasia, confusion / leptomeningeal biopsy
Neurosarcoidosis (probable) / left optic nerve / orbital sarcoidosis / established pulmonary sarcoidoses
Neurosarcoidosis (possible) / meningitis, myelitis / patchy meningeal contrast enhancement on MRI typical of neurosarcoidosis; hypoglycorrhachia; no evidence of tumour or infection; steroid responsiveness
Neurosarcoidosis (definite) / meningoencephalitis / leptomeningeal biopsy
Neurosarcoidosis (probable) / myelopathy / concurrent transbronchial biopsy-proven systemic sarcoidoses
Neurosarcoidosis (definite) / hydrocephalus, meningoencephalitis / endoscopic ependymal biopsy
Neurosarcoidosis (probable) / cerebellar relapse / established lymph node biopsy-proven systemic sarcoidoses
Neurosarcoidosis (possible) / bilateral optic neuropathy, myelopathy, left facial nerve palsy / meningeal + ependymal patchy contrast enhancement on MRI typical of neurosarcoidosis; no evidence of tumour or infection; steroid response
Neuro-Sjogren's / cognitive decline, myelopathy / sicca symptoms; anti-Ro antibodies; CSF Type II oligoclonal bands
NMDA / meningoencephalitis, hallucinations / anti-NMDA receptor antibodies; non-paraneoplastic
NMDA / encephalopathy with behavioural disturbance and dystonia, progressing to mutism / anti-NMDA receptor antibodies; ovarian teratoma
NMO / right optic neuritis, cervical myelitis / positive anti-aquaporin 4 antibodies
NMO / relapsing bilateral optic neuritis, myelitis / positive anti-aquaporin 4 antibodies
NMO / right optic neuritis, longitudinally extensive myelitis from C6 to conus / opticospinal presentation (anti-aquaporin 4 antibody negative)
NMO / right optic neuritis, longitudinally extensive cervical myelitis / opticospinal presentation (anti-aquaporin 4 antibody negative)
NMO / bilateral optic neuritis, longitudinally extensive cervical myelitis / opticospinal presentation (anti-aquaporin 4 antibody negative)
NMOSD / relapsing optic neuritis / positive anti-aquaporin 4 antibodies
NMOSD / relapsing longitudinally extensive cervical myelitis / positive anti-aquaporin 4 antibodies
NMOSD / longitudinally extensive thoracic myelitis / positive anti-aquaporin 4 antibodies
NMOSD / relapsing longitudinally extensive thoracic myelitis / positive anti-aquaporin 4 antibodies
Opsoclonus-myoclonus / opsoclonus / cause not identified
Opsoclonus-myoclonus / opsoclonus-myoclonus / paraneoplastic (thymic carcinoma)
Post-infective / acute rhombencephalitis / pneumonia 3 weeks before
Post-infective / acute cerebellar syndrome / flu-like illness 2 weeks before
Post-infective / acute cerebellar syndrome / flu-like illness 1 month before
Radiologically isolated syndrome / memory problems, no relapsing or progressive symptoms suggestive of MS yet / lesions typical of demyelination on MRI (fulfilling Barkhof’s criteria); normal physical examination, CSF & evoked potentials
Stiff person syndrome / lower limb and axial ridigity & spasms, anxiety, Type I diabetes / positive anti-GAD antibodies; response to diazepam; fulfilled Dalakas criteria
VGKC encephalitis / limbic encephalitis, hyponatraemia, seizures / positive anti-VGKC antibodies
VGKC encephalitis / limbic encephalitis, seizures / positive anti-VGKC antibodies
VGKC encephalitis / limbic encephalitis / positive anti-VGKC antibodies
VGKC encephalitis / limbic encephalitis, hyponatraemia, seizures / positive anti-VGKC antibodies

NB Two cases of CIDOMS without a definite diagnosis were categorized as “atypical MS” since a diagnosis of MS was possible but not made due to highly atypical features (Miller DH et al. Multiple Sclerosis 2008;14:1157–1174). The two lymphoma cases were categorised as CIDOMS since there was evidence of a CNS inflammatory process and it was difficult to distinguish between the effects of lymphomatous invasion and the associated autoimmune / inflammatory phenomena.

Table e-2Unclassified cases

DIAGNOSIS / CLINICAL PICTURE / INVESTIGATIONS POINTING TOWARDS AN INFLAMMATORY CAUSE*
Unclassified / one episode of meningoencephalitis / cerebral white matter signal change with linear contrast enhancement; leptomeningeal contrast enhancement; lymphocytic pleocytosis (67 mononuclears / mm3); elevated CSF protein (1387 mg/l) and CSF/serum albumin ratio (0.026)
Unclassified / progressive cerebellar ataxia and multiple cranial neuropathies / extensive signal change in rhombencephalon with some contrast enhancement; context of IgM lambda and IgG kappa paraproteinaemia; normal CSF
Unclassified / chronic headache and not progressive left-sided sensory deficit / white matter high signal change not typical of demyelination; CSF Type II oligoclonal bands; mild CSF pleocytosis (4 mononuclears / mm3); elevated CSF/serum albumin ratio (0.007) and IgG index (0.79)
Unclassified / progressive right hemisensory loss & dysphasia / progressive white matter high signal changes left frontoparietal region with consequent atrophy; mild pleocytosis (5/mm3), elevated CSF protein (537mg/l); elevated CSF/serum albumin ratio (0.009) and IgG index (1.27); Type II oligoclonal bands; left parietal cerebral biopsy showed perivascular lymphocytic inflammation and parenchymal microglial / astrocytic activation with no evidence for demyelination; vasculitis or infection
Unclassified / fluctuating right hemisensory loss, weakness and incoordination 2 months after starting adalimumab for Crohn’s disease# / right-sided solitary enhancing cerebellar lesion with subsequent improvement; CSF pleocytosis (4 polymorphs, 3 mononuclears / mm3); elevated IgG index (0.64)
Unclassified / self-limiting episode of encephalopathy / normal MR brain; CSF pleocytosis (18 mononuclears, 2 polymorphs / mm3)
Unclassified / self-limiting episode of encephalopathy / high signal in bilateral white matter and leptomeninges with contrast enhancement of the latter; elevated CSF protein (800 mg/l) and CSF/serum albumin ratio (0.018)
Unclassified / encephalopathy, seizures / extensive bilateral white matter signal change; elevated CSF protein (770mg/l); CSF Type II oligoclonal bands
Unclassified / transverse myelitis / ischaemic lesions in basal ganglia and brainstem; contrast enhancing high signal cervical cord lesion at C4; CSF pleocytosis (2 polymorphs, 4 mononuclears); elevated CSF protein (972 mg/l); CSF/serum albumin index (0.012) and IgG index (1.06); CSF Type IV oligoclonal bands
Unclassified / encephalopathy, near-synchronous onset with relapsing polychondritis / patchy high signal change in cerebral cortex, white matter and amygdalae with contrast enhancement in places; CSF pleocytosis (18 mononuclears, 7 polymorphs / mm3); elevated CSF protein (607 mg/l), CSF/serum albumin ratio (0.011) and IgG index (0.88)
Unclassified / progressive spastic quadriparesis, ataxia & cognitive decline / extensive bilateral confluent high signal change in cerebral white matter with patchy brainstem involvement; CSF pleocytosis (46 mononuclears / mm3, elevated CSF protein (1398 mg/l); CSF/serum albumin ratio (0.019) and IgG index (2.51); CSF Type II oligoclonal bands; brain biopsy: chronic leukoencephalitis with perivascular T cell infiltration and parenchymal microglial activation and astrocytic reation
Unclassified / rhombencephalitis with multiple brainstem signs and right-sided hemisensory / motor deficit / 3 brainstem lesions, one of which exhibited contrast enhancement; elevated CSF protein (652 mg/l) and CSF/serum albumin ratio (0.014)
Unclassified / 6 month illness with fluctuating left-sided incoordination, left upper limb involuntary movements, headache, dysphasia, dysarthria, memory problems, disinhibition, emotional lability / multiple areas of high signal involving grey and white matter of cerebral hemispheres and brainstem, with contrast enhancement in places, with multiphasic evolution over 5 months apparent on sequential MRI scans; CSF pleocytosis (3 mononuclears / mm3); elevated CSF IgG index (0.68)
Unclassified / uveomeningitis / inflammation of anterior segment of the eye on slit lamp examination; MRI normal apart from left thalamic infarct of uncertain relation to current illness; CSF pleocytosis (55 mononuclears, 5 polymorphs / mm3); elevated CSF protein (1113 mg/l), CSF/serum albumin index (0.019) and IgG index (0.76)
Unclassified / right optic neuritis 2 weeks after flu / high signal / contrast enhancement in right optic nerve, right medulla, left cerebral peduncle; CSF pleocytosis (31 mononuclears / mm3); elevated CSF protein (702mg/l); elevated CSF/serum albumin ratio (0.009) and IgG index (0.59); negative anti-aquaporin 4 antibodies
Unclassified / one episode of transverse myelitis & left optic neuropathy / high signal lesion brainstem and upper cervical cord, CSF pleocytosis (4 mononuclears / mm3); elevated CSF protein (620mg/l); CSF Type II oligoclonal bands; evoked potentials not supportive of demyelination and anti-aquaporin 4 antibodies negative

* Extensive investigation for inflammatory / infectious / genetic diagnoses negative. For cerebrospinal fluid (CSF), mention is only made of abnormal results (cell count, cytology, glucose (<2/3 blood glucose), protein (>500mg/l), CSF/serum albumin ratio (>0.006), IgG index (>0.58), culture, viral, bacterial & fungal studies and oligoclonal bands).Neural antibody testing available at the time was as follows: NMDA, VGKC, VGCC, gangliosides, Hu, Yo, Ri, Ma, Amphiphysin, CRMP/CV2, Ro, aquaporin-4, glutamic decarboxylase, as well as indirect immunofluorescence on monkey brain performed by a highly experienced senior clinical scientist. Although indirect immunofluorescence might be expected to pick up immunoreactivity that was not defined at the antigenic level, this is a limitation and newer better tests may account for some undiagnosed cases in the future.

# Adalimumabwas stopped as soon as the patient developed neurological symptoms, and no other TNF alpha inhibitor or biologics have been utilized since. Yet she continues to have flare-ups of the right-sided sensory symptoms and the single cerebellar lesion persists, with contrastenhancement reduced but still present, 3 years after cessation of adalimumab. It is possible that TNF alpha inhibitor use unmasked an unclassifiable CIDOMS which was latent.

Abbreviations:

ADEM, acute disseminated encephalomyelitis; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CIS, clinically isolated syndrome; CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; GAD, glutamic acid decarboxylase; IgG, immunoglobulin G; MRI, magnetic resonance imaging; MS, multiple sclerosis; NMDA, N-methyl D-aspartate; NMO (SD), neuromyelitis optica (spectrum disorder); VGKC, voltage-gated potassium channel complex.

Table e-3Number, percentage and biennial resource use cost of CIDOMS patients (total and mean per patient) by their final diagnostic categories

FINAL DIAGNOSTIC CATEGORY / NUMBER / PERCENTAGE / BIENNIAL RESOURCE USE (£)
TOTAL / MEAN
Unclassified / 16 / 25 / 89,787.84 / 5,611.74
Neurosarcoidosis / 9 / 14 / 96,535.23 / 10,726.14
Neuromyelitis optica / 9 / 14 / 29,358.85 / 3,262.09
Cerebral vasculitis / 4 / 6 / 74,628.16 / 18,657.04
Anti-VGKC encephalitis / 4 / 6 / 26,099.77 / 6,524.94
ADEM / 3 / 5 / 28,299.23 / 9,433.08
Post-infective / 3 / 5 / 10,411.45 / 3,470.48
Anti-NMDA receptor encephalitis / 2 / 3 / 94,570.75 / 47,285.38
Paraneoplasia in lymphoma / 2 / 3 / 24,666.69 / 12,333.35
Opsoclonus-myoclonus / 2 / 3 / 13,363.33 / 6,681.67
Neuro-Behçet’s / 2 / 3 / 9,477.89 / 4,738.95
Atypical MS / 2 / 3 / 5,426.99 / 2,713.50
CRION / 1 / 2 / 4,727.77 / 4,727.77
Anti-Hu syndrome / 1 / 2 / 4,155.61 / 4,155.61
Lymphocytic hypophysitis / 1 / 2 / 3,312.27 / 3,312.27
Neuro-Sjögren's / 1 / 2 / 2,552.76 / 2,552.76
Stiff Person Syndrome / 1 / 2 / 1,825.73 / 1,825.73
Radiologically isolated syndrome / 1 / 2 / 1,208.86 / 1,208.86
TOTAL / 64 / 100 / 520,409.18 / N/A

Abbreviations: VGKC, voltage-gated potassium channel complex; ADEM, acute disseminated encephalomyelitis; NMDA, N-methyl D-aspartate; CRION, chronic relapsing idiopathic optic neuritis; N/A, not applicable

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3.Calabrese LH, Mallek JA. Primary angiitis of the central nervous system. Report of 8 new cases, review of the literature, and proposal for diagnostic criteria. Medicine (Baltimore) 1988;67:20-39.

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8.Krupp LB, Tardieu M, Amato MP, et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler 2013;19:1261-1267.

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