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We present an interesting neurological case reinforcing our understanding of neurological anatomy, diagnosis and management but, most importantly, of compassion and humanity.
A 14-year-old left-handed young man of African heritage attended the emergency department with a 4-week history of left-sided limp and 3 days of facial asymmetry and slurring of his speech. He reported a decline in the quality of his handwriting at school during this period. He had no history of fevers, trauma, pain, headaches, vomiting, neck stiffness, visual problems, breathing or swallowing difficulties. He had a background of alopecia totalis treated with topical steroid cream. He had no other medical history, medications nor allergies. He was fully immunised and family and social histories were unremarkable with no recent travel.
On examination, he demonstrated mild left-sided facial weakness sparing the forehead and slow, slurred speech. The remaining cranial nerves were normal. In his left upper limb, he had dysdiadochokinesia, marked past pointing, pronator drift and 4/5 power with normal tone and reflexes. He had a left-sided hemiplegic gait with an upgoing plantar reflex on the left and normal tone. His right upper and lower limb examinations were normal. Sensation was normal throughout. Remaining systems examinations and vital signs were normal.
Multiple choice questions
Which area(s) of the nervous system are affected?
Cortex and cerebellum.
Peripheral nerves (including cranial nerves).
c. The signs localise to the upper motor neuron pathway of the right hemisphere and left cerebellum.
What is the most definitive next investigation?
Basic blood tests (full blood count, renal/liver/bone profiles and C reactive protein).
c. Brain MRI is most likely to provide contributory information. If presenting to a hospital without MRI scanning capacity, such a case of subacute focal neurology would warrant semiurgent transfer. If the presentation were more acute, then—in accordance with Royal College of Paediatrics and Child Health guidance on Childhood Stroke1—CT-angiography should be performed within an hour of presentation. An acute encephalopathic picture would warrant an urgent brain MRI to assess for possible acute disseminated encephalomyelitis (ADEM). In the context of focal neurology, safety of proceeding to lumbar puncture should of course be assessed with prior neuroimaging.
He was admitted to the ward for further investigations. MRI findings are shown in figure 1.
Which of the following processes should be included in the differential diagnosis? (Select all correct answers.)
Inflammatory (including demyelinating and autoimmune).
a, b, c, d and e. The differential is extremely wide and a structured approach to investigation is therefore crucial. While less relevant in this case, traumatic brain injury is common and should not be neglected.
What is the most important next investigation?
MRI of the whole spine.
c. A lumbar puncture with cerebrospinal fluid (CSF) analysis is likely to be most helpful in assessing the probability of infection as a common and treatable cause, may identify inflammation or suggest malignant disease. All tests, however, should be done and a paediatric neurology opinion should be sought at this stage.
CSF analysis was unremarkable with normal microscopy, biochemistry, bacterial culture, viral PCR and paired oligoclonal bands. CSF cytospin analysis was unsuccessful. Comprehensive bloodwork, including infective and autoimmune screens, were unremarkable. Anti-myelin oligodendrocyte glycoprotein (MOG) antibodies were negative. An MRI of the whole spine was normal. An electroencephalogram showed cerebral dysfunction most prominent over the right temporal region. An ophthalmology review revealed normal vision and fundi. The most probable differential diagnoses at this stage were an acquired demyelination syndrome (ADS) of the CNS or a neoplastic process.
Which management option is most appropriate at this stage?
Broad-spectrum antibiotics and antivirals.
Intravenous normal immunoglobulin.
Inpatient surveillance with repeat MRI.
b. The suspicion of acute inflammatory/demyelinating disease was sufficiently high to warrant a trial of immunosuppressive therapy (intravenous steroids in the first instance). One must be wary that a neoplastic process remains in the differential and may also transiently respond to steroid therapy, particularly CNS lymphoma. Brain biopsy is a reasonable option in the setting of diagnostic uncertainty. This decision should be made in discussion with tertiary paediatric neurology and neurosurgery. Infection is unlikely at this stage.
Aquired Demyelination Syndromes (ADS)
ADS are an important spectrum of diseases that all paediatricians should be aware of. They present with acute or subacute CNS symptoms and signs that may be focal or general. Their presumed aetiology is of a post-infective autoimmune process, and they generally respond well to immunosuppressive therapy (acutely high-dose steroids, inravenous normal immunoglobulin or plasmapheresis). ADS are uncommon, with an incidence in the UK of approximately 10 per million/year. The syndromes and their relative frequencies are ADEM (32%), neuromyelitis optica (NMO, 1%), optic neuritis (25%), transverse myelitis (21%) and other clinically isolated syndromes (21%, which can be multifocal or unifocal).2 In paediatrics, they frequently occur as one-off monophasic events, but they can also be multiphasic or relapsing (relapsing acquired demyelination syndrome)—that is, multiphasic ADEM, multiphasic neuromyelitis optica spectrum disorder (NMOSD) or multiple sclerosis. There are now well-defined diagnostic criteria for these classifications based on clinical, MRI and serological findings.3 Multiphasic disease frequently warrants treatment with long-term immunomodulatory therapy supervised by a paediatric neurologist.
A recent development in ADS has come with the discovery of an additional serological marker—anti-MOG antibodies. It has long been known that anti-aquaporin 4 (AQP4) antibodies are strongly associated with NMOSD. It is now coming to light that anti-MOG antibodies are also highly specific in children with ADS.4 Anti-MOG antibodies are present in approximately 30% of children with ADS and especially in younger children. They can be present in any clinical syndrome but are particularly associated with ADEM (~50% anti-MOG antibody positive) and anti-AQP4-negative optic neuritis (~35%).5 Anti-MOG antibody disease appears to be a distinct entity with characteristic radiological and other features.6 Appropriate testing for anti-MOG antibodies is vitally important because a positive result carries prognostic significance—most pertinently, an increased rate of relapsing disease that may well warrant, and benefit greatly from, treatment.5 The test has an approximate turnaround time of 1–2 weeks and cost of £50.7 A diagnostic algorithm for ADS in children has recently been developed that advises how to use antibody testing appropriately,8 but the key message for the non-specialist is to discuss all cases of suspected or possible ADS with a paediatric neurologist. Multiple long-term immunomodulatory treatment options exist for anti-MOG antibody disease but inravenous normal immunoglobulin is emerging as the preferred option.9
Our patient was treated with intravenous methylprednisolone 30 mg/kg (maximum dose 1 g) once per day for 5 days. On completing this regimen, there had been no clinical response. He continued an oral steroid wean and was referred to physiotherapy, occupational therapy, and speech and language therapy for ongoing assessment and support. A repeat brain MRI was performed on day 6 to assess for any radiological response but demonstrated further disease progression.
Given the failure to respond to immunosuppressive therapy, an atypical CNS malignancy was now a probable diagnosis and, in discussion with neurosurgery, it was agreed that a brain biopsy should be performed to guide further management. In the meantime, treatment with 2 g/kg intravenous normal immunoglobulin over 2 days was completed to cover for a resistant inflammatory process. A brain biopsy was undertaken on day 25 of admission. The histopathology and molecular analysis of the brain lesion biopsy showed features consistent with a histone H3G34R-mutant high-grade neuroepithelial tumour (figure 2). This is a recently described entity bearing histone H3F3A point mutations at G34, occurring in teenagers and young adults and being mostly confined to the cerebral hemispheres.10 These tumours are not recognised as a separate tumour in the current WHO (2016) classification of CNS tumours but are likely to be included in future classifications. These tumours bear poor prognosis and may have been previously regarded as glioblastoma or CNS primitive neuroectodermal tumours equivalent to WHO grade IV tumours. The key genetic and epigenetic features are diagnostically helpful and may guide in precision treatment.
Following staging images of his thorax and pelvis (normal), our patient was referred to a neuro-oncology centre, where the diagnosis of incurable cancer was discussed with his mother. Naturally, the disclosure of the diagnosis to the patient presented an exceedingly difficult issue for his mother and treating team alike. The support of a multidisciplinary team, including palliative care physicians and clinical nurse specialists, oncology clinical nurse specialists and psychologists, was enlisted to assist with this process and provide ongoing management.
The aims of palliative care are, first and foremost, to improve quality of life and ameliorate patient suffering, rather than preserving life to postpone death at all costs. Considering the child’s psychosocial and spiritual needs while supporting them and their family members through each step in the palliative care journey is essential.
Prognostic disclosure in life-limiting paediatric conditions is challenging but absolutely necessary. Studies show that children have fewer coping strategies while experiencing similar levels of stress11 and that open communication improves outcomes12 13—reducing distress,11 12 enhancing trust in clinicians,14 adherence to treatment,15 emotional well-being and coping skills15–17—while lowering depression rates.18 Furthermore, informed patients make more thoughtful considerations for future plans, hospice care and treatment directed at lessening suffering.19 20 Multiple areas should be considered for an optimal compassionate disclosure.
Initiating a disclosure
Conversations are likely to take place when an illness is first recognised, during reviews or deterioration, and when approaching the end of life.
An appropriate named clinician should coordinate care who is acceptable to the family. They should continue an ongoing therapeutic relationship with patient and family, be available for repeated conversations and have up-to-date knowledge.21
Establish the aims of a conversation by asking the patient (even young children) and family how much they wish to know and what involvement they want in decision making. Remind them that they will be told the truth and that, though their thoughts are integral, they are not expected to make decisions alone.22
Optimising communication and individual considerations
Multiple conversations may be required on a schedule that suits the child.
Carefully consider attendees. Adolescents at times may need their family to be absent; they should be provided with choices and always have their autonomy respected. Also consider including particular members of the multidisciplinary team (e.g. play, psychology, school and religious leaders).
Tailor communication, considering developmental age, cultural and personal factors, as well as previous experiences of death or illness. This may involve one-to-one discussions, play with toys, art, writing and digital media.21 23
Clinicians must look for cues that the child needs more information (e.g. appearing anxious), as children may not ask questions directly.24
Specifically enquire after fears or concerns—it is often possible to offer reassurance (e.g. the efficacy of pain relief). If the child and/or family wish for prognostication around likely timing of death, this should be answered openly (acknowledging an appropriate degree of uncertainty).
Allow time for discussion and questions.
Provide realistic hope and plentiful support.
Family and cultural considerations
Studies show that healthcare staff view cultural differences as an obstacle to optimal paediatric palliative care,25 so it is vital that practitioners deconstruct their own beliefs and preconceptions and consider the detrimental effects of cultural stereotyping on care delivery.26
Every child should be assessed and supported spiritually: probing understanding about life and death, suffering and pain, hopes and wishes and previous experiences of illness and trauma.
Offer involvement of community or religious leaders and extended family and psychological support as appropriate.
Openness is paramount, but in some cases, it is appropriate to ask families how much they feel a child should be told.
Adolescents must be involved in decision making as their wishes are often not known to their family.27
In cases where disagreements occur, clinicians must discuss that non-disclosure removes the child’s autonomy around decision making and preparations for the end of their life25 and that younger children, as they develop, will adopt the role of decision maker from parents and medical staff, and this should be cultivated from an early age. Parents often want to protect their children from pain, but a climate of open and honest communication helps everyone supporting the child and thus enables the child and family to make the right decisions about their care.
Ultimately, following considered discussion, our patient proceeded to palliative radiotherapy and chemotherapy with temozolomide (an alkylating agent used to treat some brain tumours). He received vital ongoing supportive care from a multidisciplinary team.
This case was unexpectedly rare and complex. It reinforces many important principles of diagnosis and management but also highlights how communication and holistic caregiving are as integral (if not more) in the practice of good medicine. We are grateful to the patient and his family for enabling us to share his case and subsequent learning. Our patient and his family were resilient, positive and kind throughout this most vulnerable and difficult experience.
Contributors JMH and CD contributed equally to this paper. LH supervised the report. AM and AD produced the histopathology images and report. FC produced the radiology images and report.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Parental/guardian consent obtained.
Provenance and peer review Not commissioned; externally peer reviewed.