Article Text

Download PDFPDF
Spotting the wolf in sheep's clothing
  1. A P Basu1,
  2. S M George2,
  3. G Udpa3,
  4. M Friswell4,
  5. A M Devlin2,
  6. M Abinun2,
  7. K K Pang2
  1. 1Sir James Spence Institute, Royal Victoria Infirmary, Newcastle upon Tyne, UK
  2. 2Newcastle General Hospital, Newcastle upon Tyne, UK
  3. 3Young Peoples Unit, Prudhoe Hospital, Prudhoe, Northumberland, UK
  4. 4Royal Victoria Infirmary, Newcastle upon Tyne, UK
  1. Correspondence to Dr Anna Basu, Level 3, Sir James Spence Institute, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK; a.p.basu{at}ncl.ac.uk

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Jane, a 13-year-old girl, had a 4-week history of abnormal left limb movements and falls. The first problem noted was a high stepping gait on the left which resolved over a few days. Several falls, presumed to be vasovagal faints, ensued and a few days prior to her admission she collapsed after her left leg ‘gave way’. Following this collapse she had persisting left arm weakness and speech difficulties. The general practitioner was concerned she had suffered a stroke and he referred her to hospital for further assessment.

The history obtained by the registrar established Jane had been born prematurely at 27 weeks gestation but the pre-, peri- and postnatal course had otherwise been uneventful. She was described as having mild learning difficulties but was in mainstream education with support. In the previous year, she had been seen by the Child and Adolescent Mental Health Service (CAMHS) because of mood swings and some self-harming behaviours. These were attributed to bullying at school and a bereavement reaction to the death of her mother 5 years earlier. With her current presentation, Jane had developed a right hand preference having previously been left hand dominant. She could no longer walk upstairs and had to crawl up while holding on to the banister with her right hand. During the day, her family thought she appeared confused and she would talk for prolonged periods of time, as if to another person, when no-one else was present. She had not slept well for several days and had started to wander about the house, looking for objects which she thought had been lost. There was also a history of fatigue and moderate weight loss in the preceding months.

Comment

  • ▶. Taking a detailed medical and psychosocial history is the first step to enable the formulation of hypotheses which may then be confirmed or refuted by the physical examination.

  • ▶. The left sided motor dysfunction was suggestive of focal, right sided, cortical pathology. Right hemisphere dominance is present in 27% of strongly left handed people1 and therefore the speech difficulties could also be explained by a right sided lesion.

  • ▶. In contrast, the cognitive and mood disturbances described were suggestive of a more global disturbance of cerebral function.

  • ▶. The additional history of learning difficulties and previous involvement with CAMHS placed Jane at higher risk of psychiatric comorbidity,2 adding a further dimension to the diagnostic formulation.

  • ▶. The time course of events was suggestive of a process that was still evolving.

On examination Jane was noted to have marked emotional lability and a variable degree of expressive and receptive dysphasia. She complained of abnormal sensations in her left leg and face, while involuntary facial movements were seen on the left, which worsened when she became agitated or distressed. She also had some jerky movements and abnormal posturing of the left arm and leg, but neurological examination was otherwise normal. General medical examination was unremarkable and there was no rash, meningism or fever.

The physical examination confirmed the findings obtained from the history, reinforcing the impression that the causal process was neurological in origin. However, the combination of subjective and objective disturbances meant that the registrar found it difficult to be confident about the nature of the pathology so Jane was admitted for observation. Given that she had focal, albeit intermittent disturbances, a CT brain scan was requested to look for structural causes that may have required urgent treatment, while a set of routine bloods was obtained to rule out infective and metabolic causes (table 1).

Table 1

Results of initial investigations

During her stay Jane was noted to have difficulty following instructions and required assistance with activities of daily living, such as dressing, which she would normally have managed alone. While her presentation generally corroborated the history given, there were occasions when the timing of some events was perceived to be unusual. Thus exacerbations of bizarre unsteadiness or jerky limb movements would sometimes occur when in the presence of staff or family. Such incidents could, at times, be terminated on request and the possibility of a conversion disorder was raised. Given the diagnostic difficulties resulting from Jane's neurological and behavioural abnormalities, the neurology team was asked to take over her care.

Comment

  • ▶. When a patient presents with multiple symptoms which are difficult to reconcile with clinical or investigational findings, the possibility of a conversion disorder should be considered. This is defined as a disturbance of body function characterised by neurological, sensory or motor symptoms where known medical explanations do not explain or fail to account for the severity of the patient's impairment.3 The symptoms are experienced as involuntary, distressing or disabling. This is in contrast to a factitious disorder where there is intentional or conscious simulation of symptoms.3

  • ▶. Conversion disorders are commoner in girls and when there are known family stressors, with loss of attachment figures being a common antecedent event4 and unhappiness at school a common precipitating factor.5 Presentation is often with disturbed voluntary motor function (including bizarre gait), sensory symptoms and pseudoseizures.

  • ▶. Factors not in support of a diagnosis of conversion disorder in Jane included the severe sleep disturbance and fluctuating cognitive impairment as well as the combination of dysphasia and change in hand preference, all of which in combination suggested cortical organic pathology.

Jane was seen by the consultant neurologist who initially found her difficult to assess because her level of co-operation varied and she would at times withdraw by means of eye closure and absence of communication. It was therefore not possible to perform a complete examination in one session and she had to be seen over several days. During repeated motor assessment, it became clear that Jane had occasional left arm chorea/dystonia which impaired the quality of her arm and finger movements. She had a weaker left hand grip and increased left biceps, triceps and brachioradialis reflexes. However, she could now walk stably and her gait was normal. When she could be encouraged to converse, Jane had a mild dysarthria as well as an expressive and receptive dysphasia. On occasions, however, her speech was out of context (eg, “Do you have to pay to go swimming here?”) or consisted of incomprehensible mumblings. During the assessments Jane varied from having a muted, flat affect to being agitated and aggressive. She fluctuated in her degree of orientation in time, person and place and she displayed episodes of irrational behaviour consisting of purposeless wandering, kicking and thrashing. Opinions from a consultant psychologist and speech and language therapist were also sought and were in keeping with the above findings, although formal assessment was not possible at this stage. In conclusion, Jane was thought to have a fluctuating neurological process consisting of focal motor as well as global speech and cognitive impairment.

Comment

  • ▶. Performing a neurological examination in a young person with behavioural disturbances is not easy but it has to be approached in a systematic manner and, if inconclusive, repeated on multiple occasions to enable objective interpretation of the findings. Critical observation of spontaneous activity can in itself provide valuable information.6

  • ▶. Jane had features of a confusional state or delirium. Delirium is a neuropsychiatric disorder characterised by: (1) acute onset and fluctuation; (2) a disturbance of consciousness with reduced ability to focus, shift or maintain attention; and (3) a change of cognition with memory deficit, disorientation, language disturbance, perceptual disturbances or hallucinations; and (4) is caused by the direct physiological consequences of a general medical condition.3 Psychotic symptoms may coexist in up to 43% of adult cases.7 The disturbance of attention and consciousness are key in discriminating between delirium and dementia, whereas cognitive difficulties will occur in both.

  • ▶. In adults, several tools exist for the assessment of delirium, but few have been validated in children. In all cases, the process should begin with taking a good history to determine the onset and fluctuating course. A history of sleep–wake cycle disruption is often elicited. Deficits in maintaining attentional focus and restlessness can be gauged during a period of observation or interaction. It may be possible to establish whether he or she is orientated in person, place and time by asking some simple questions, but cognitive changes can be difficult to assess in a delirious patient. Any cognitive assessment used must take into consideration the premorbid level of functioning. Listening to the carers' comments about how the person's behaviour and abilities have changed may provide additional information when formal neuropsychological testing is not possible.

  • ▶. There are many causes of delirium, all of which have to be considered within the context of the clinical presentation8 9 (table 2). In children the commonest cause is infection.10 Although the list of other possible causes is long, an initial screen comprising simple or inexpensive tests could include urine dipstick and microscopy, urine toxicology, urine organic acids, full blood count, C reactive protein (CRP), glucose, blood gas, urea and electrolytes, magnesium, ammonia, lactate, liver function, thyroid function and bone profile. This can exclude a large number of easily treatable conditions and allow the clinician to adopt a more focused approach later on. Early consultation with neurology is important when the diagnosis is unclear.

  • ▶. Management of patients with delirium who may be both very ill and agitated or withdrawn can be a challenge and in such cases liaison with colleagues from child psychiatry is advisable. The American Psychiatric Association produced guidelines in 199911 which, although in need of an update, still constitute very sound suggestions (box 1).

Table 2

Some important causes of confusional state or delirium

Box 1 Management of delirium

  • ▶. Identify the aetiology and treat the underlying condition

  • ▶. Monitor vital signs and stabilise medically

  • ▶. Review medication chart and discontinue non-essential drugs

  • Assess and manage the risk of harm to self and others

    • ▶. Agitated, disorientated patients may become violent or may wander and become lost. Remove dangerous items from their environment and ensure adequate surveillance. Pharmacotherapy may be needed. Restraint is to be avoided if at all possible

  • ▶. Monitor psychiatric status

  • ▶. Establish rapport with the family, obtain further history and provide explanation and support

  • Provide an appropriate environment

    • ▶. Both overstimulation and understimulation can be unhelpful. A quiet side room, optimum lighting levels and a clear routine for each day will help. Familiar faces (family and staff) and family photographs and favourite toys from home are likely to be reassuring. Frequent re-orientation (including provision of a clock and calendar for older children) is important

    • ▶. If the child wears glasses or has a hearing aid, ensure they are used, as sensory deprivation aggravates delirium

  • ▶. Antipsychotic medication (either typical antipsychotics like haloperidol or newer atypical antipsychotics such as risperidone) can alleviate symptoms of delirium. Benzodiazepines such as lorazepam can be helpful but sometimes cause paradoxical disinhibition rather than sedation. Be aware of the side-effect profiles of drugs used

  • ▶. Provide explanation and ongoing support as needed to the young person when the delirium has ceased

  • ▶. A liaison psychiatry service can provide valuable advice if the child has to be managed on an acute medical ward

  • ▶. A high level of nursing support is likely to be required day and night until improvement occurs

The presence of fluctuating, focal neurological signs in the context of more global cognitive and behavioural impairment led to the formulation of the following differential diagnoses: focal epilepsy, a vasculopathy, an autoimmune disorder, emerging psychosis or a conversion disorder (table 3).

Table 3

Differential diagnosis of fluctuating focal neurological signs with global cognitive impairment

Jane's symptoms and the differential diagnoses were discussed on the grand round, along with the factors which supported or refuted the hypotheses (table 3). Given that progression had occurred over a period of weeks, an additional comment was whether the symptoms and signs were a reflection of true cognitive decline (and thus symptomatic of neurodegenerative disease) or instead, represented pseudo-regression, ie, a temporary and reversible decline in cognition. Pseudo-regression can be seen in a number of circumstances, such as non-convulsive status epilepticus, depression or stressful life events particularly on a background of learning difficulties.12 Senior members of the team also reminded trainees not to forget that non-organic disorders can coexist with physical illness – the assessment is challenging and misdiagnoses can occur.13

A practical issue was raised regarding whether, in the context of a young person with delirium for which there was a broad differential diagnosis (table 2), it would be better to undertake a large number of investigations in one single procedure and minimise distress, or to adopt a sequential approach to investigation starting with the most likely conditions. A targeted set of investigations was therefore performed based on the clinical presentation with the aim of undertaking further tests in the light of subsequent findings.

Comment

  • ▶. While it is important to minimise distress to the patient and forethought can reduce the number of invasive investigations performed, it is also vital to realise that searching for a large number of very rare conditions (such as many neurodegenerative diseases) which are improbable in the clinical context is more likely to lead to false positives rather than a diagnosis.12

  • ▶. A compromise can often be achieved by both adopting an evidence-based approach to the differential diagnosis14 and freezing/storing certain samples, for example, cerebrospinal fluid (CSF), for later re-evaluation.

An EEG and MRI of the brain followed by lumbar puncture were requested because of Jane's cognitive changes, movement disorder and focal neurological signs. Given the additional constitutional features, an autoantibody screen was sent, while the full blood count, inflammatory markers and biochemistry screen were repeated.

The EEG showed a preserved background rhythm (8–9 Hz alpha) but an active slow wave focus (<4 Hz delta) in the right centrotemporal region (figure 1). This was consistent with focal cortical dysfunction rather than epilepsy and raised concerns with regards to a possible structural lesion despite the normal CT scan result. MRI of the brain was, however, normal and MR angiography did not identify any signs of vasculopathy. A lumbar puncture was performed after the imaging and examination of CSF excluded infection as a cause.

Figure 1

EEG showing persistent asymmetry of background activity with high amplitude, focal slowing over the right hemisphere.

From the repeat blood tests sent, the biochemistry screen, CRP and erythrocyte sedimentation rate (ESR) were normal. However, the mild lymphopenia persisted at 1.18×109/l and antibodies to double stranded DNA (dsDNA-Ab) were raised at 74 IU/ml (negative: <15; borderline: 15–40; positive: 41–300; strongly positive: >300 IU/ml). This result was very suggestive of systemic lupus erythematosus (SLE) and an urgent rheumatology opinion was sought. The rheumatology consultant reviewed the findings and elicited additional supportive features in the history, such as joint pains, mouth ulcers, malaise, tiredness and some hair loss. Four of the American College of Rheumatology (ACR) classification criteria for SLE (table 4) were identified comprising: (1) a history of oral ulceration; (2) a haematological disorder (mild anaemia and lymphopenia); (3) an immunological disorder (positive dsDNA-Ab); and (4) a neurological disorder (acute confusional state).

Table 4

Revised American College of Rheumatology classification criteria for systemic lupus erythematosus33

A malar rash (figure 2) was not prominent (although this became apparent several months later, as did livedo reticularis) and there were no overt arthritis, serositis or ECG abnormalities. The ESR was not raised and complement levels (C3/C4) were not severely depleted as may occur during active disease, although C4 was borderline low. Unusually, antinuclear antibodies (ANA) were negative, but a repeat dsDNA-Ab was again positive at 53 IU/ml, and extractable nuclear antigens (anti Ro and La) became borderline positive later in the course of the illness. As proteinuria had been detected on urine dipstick, urine microalbumin/creatinine ratio was requested and found to be elevated at 47.7 mg/mmol creatinine (normal 0–3.5 mg/mmol). Jane's blood pressure was within the normal range and the renal team advised close monitoring but no additional action was required at that stage. Subsequently renal follow-up was initiated due to worsening proteinuria.

Figure 2

Malar/'butterfly' rash in SLE. The nasolabial creases are relatively spared. Image reprinted with permission from eMedicine.com, 2009.

Systemic lupus erythematosus

SLE is a multisystem, autoimmune, connective tissue disorder in which immunological abnormalities, in particular antibodies to nuclear components, are a prominent feature. The prevalence is around 50/100 000 population, more females are affected (9 females:1 male) and up to 20% of cases can occur in children or adolescents.15 The initial presentation is often with non-specific constitutional symptoms such as fatigue, arthralgia, mood swings and weight loss, so early diagnosis can be a challenge. In particular, some of the classical findings in adult SLE (in particular malar rash and dsDNA positivity) are less common in children, whereas fatigue is more common.

If four or more of the 11 ACR criteria (table 3) are present, serially or simultaneously, the diagnosis of SLE can be made with 95% specificity and 85% sensitivity.16 Although the classification was designed to identify patients for clinical studies (thus non-specific constitutional features are deliberately not included), it also functions as a valuable checklist for individual patients. With current assays, the majority of patients with SLE are ANA positive and less than 2% are ANA negative.17 In the latter situation, when causes of false negative results have been excluded (heavy proteinuria, immunosuppression, incorrect assay), some patients who are initially ANA negative become positive several years later.17

Neuropsychiatric lupus

Immunological and renal involvement are well-known features of SLE, but neuropsychiatric complications can also occur and 19 discrete syndromes have been described in adults (ACR18). Neuropsychiatric manifestations may occur in 25% of children and adolescents with SLE, with the majority becoming symptomatic within the first year of diagnosis.19 These may coexist at any one time (figure 3) and MRI of the brain may be normal even in the presence of clear neurological abnormalities (as was the case with Jane). Single photon emission CT imaging has revealed diffuse regional cerebral hypoperfusion under these circumstances,20 while EEG can identify focal and generalised abnormalities.21

Figure 3

Spectrum of neuropsychiatric lupus manifestations in children. Reproduced with permission.19

Antineuronal antibodies and neuropsychiatric lupus

It has been known for some time that antibodies to neuronal antigens and certain ubiquitous cellular components are found in higher concentrations in the sera of SLE patients with neuropsychiatric complications. These include antiphospholipid antibodies and antiribosomal P antibodies.

Antiphospholipid antibodies

In the antiphospholipid syndrome there is a hypercoagulable state and increased risk of venous and arterial thrombosis due to the presence of antiphospholipid antibodies, namely lupus anticoagulant (a misnomer as it is not an in vivo anticoagulant) and anticardiolipin antibodies.22 In vitro, coagulation studies are prolonged because the lupus anticoagulant interferes with the assembly of prothrombinase on phospholipids. In vivo, the antibodies are usually seen as a transient and asymptomatic phenomenon following viral infections. In childhood, antiphospholipid syndrome rarely occurs as a primary condition but instead is secondarily associated with autoimmune diseases such as SLE. The presence of antiphospholipid antibodies in childhood SLE does not necessarily increase the risk of thrombotic events, but there are increased reports of neurological complications including focal seizures and chorea.22

Antiribosomal P antibodies

The presence of antibodies to three specific ribosomal proteins has been described in patients with lupus psychosis and severe depression. However, the high prevalence of mild to moderate mood and anxiety disorders in this population makes it difficult to interpret their significance.23

When investigations for the cause of Jane's neuropsychiatric presentation of SLE were performed, assays for antiphospholipid and anticardiolipin antibodies were negative and clotting studies were normal. However, she was found to be positive for anti-NMDA receptor antibodies.

Neuropsychiatric lupus, NMDA-receptor encephalitis or both?

An alternative explanation for Jane's neuro-psychiatric presentation is N-methyl-D-aspartate (NMDA)-receptor encephalitis (box 2), an autoimmune form of encephalitis first described in adult women with ovarian tumours24 but subsequently recognised in children and adolescents.25 Patients have autoantibodies to the NR1/NR2 subunits of the NMDA receptor (a ligand-gated channel involved in learning and memory). Some patients with neuropsychiatric lupus have also been described as having antibodies to dsDNA which cross-react with an epitope of the NR2 subunit of the NMDA receptor.26 27

Box 2 Autoimmune encephalitis

  • ▶. Autoimmune encephalitis is an important cause of non-infective encephalitides

  • ▶. Recently characterised mechanisms include antibodies to the voltage-gated potassium channel (causing limbic encephalitis) and antibodies to the N-methyl-D-aspartate (NMDA) receptor

  • ▶. The key features of NMDA-receptor encephalitis include personality change, cognitive impairment, reduction in speech, dyskinesia and sleep disturbance

  • ▶. In adults, encephalitis may occur as a paraneoplastic process. This is less common in children, but NMDA-receptor encephalitis has been associated with ovarian teratoma and the possibility of an occult tumour has to be considered

Jane was therefore screened for ovarian pathology and an abdominal and pelvic ultrasound was normal. Jane fulfilled diagnostic criteria for SLE, but she also possessed many of the overlapping psychiatric and neurological features described in patients with NMDA-receptor encephalitis. The pathological role of antibodies to the NMDA receptor in both conditions is an area of ongoing scientific study.

Treatment and outcome of SLE

The outcome in SLE has improved dramatically in recent decades. In 1955, 5-year survival was less than 50%, whereas now 10-year survival is over 90%.28 With better survival, it is increasingly important to consider long-term complications, including those relating to interventions. Currently there is no standard protocol for the treatment of neuropsychiatric SLE, although a Cochrane review identified one small randomised controlled trial comparing cyclophosphamide and methylprednisolone. This suggested cyclophosphamide was more effective in achieving improvement in symptoms and reduction in seizures, with no difference in adverse effects.29

Jane was initially given two courses of intravenous methylprednisolone, but there was a poor response and on the 9th day of treatment she started having seizures. Jane also became increasingly agitated, emotionally labile and aggressive. As this change in behaviour may have been a consequence of high dose steroid treatment, cyclophosphamide was started and Jane began to improve. A period of inpatient rehabilitation followed, with the involvement of speech and occupational therapists. A clinical psychologist assessed her cognitive function and mood, while liaison with schoolteachers established Jane's premorbid level of functioning. Jane's symptoms stabilised and she was discharged from hospital with further improvement of speech, mood and left arm function in the following months.

Jane remains on immunosuppressive medication with mycophenylate mofetil and is under outpatient immunology follow-up. In the event of disease progression, the use of high dose intravenous immunoglobulin and/or B cell depletion using rituximab30,,32 would be considered on the basis of positive reports from the literature for treatment of both SLE and NMDA-receptor encephalitis. Her ongoing management is multidisciplinary and she is also under review by the renal team because of heavy proteinuria. A paediatric neurologist reviews her seizure control and cognitive function, while a consultant psychiatrist monitors her behaviour and affect. Finally and importantly, a general paediatrician oversees management and is involved in liaison with the school as communication across different specialities is vital to co-ordinate care and achieve the best outcome possible.

Clinical message

  • ▶. A detailed history, combined with close observation of behaviours and systematic neurological examination, is essential when there are presenting features of neuropsychiatric disease.

  • ▶. Adopt an evidence-based, focused approach to look for medical causes.

  • ▶. Remember the complex, neurobehavioural manifestations of immune-mediated disease.

  • ▶. Patients may not fit into neat diagnostic categories; functional symptoms can coexist with organic disease and the diagnostic boundaries between conditions can be unclear.

  • ▶. Good multidisciplinary working is essential for the management of conditions affecting multiple organ systems.

Acknowledgments

The authors would like to extend our sincere thanks to the young lady in question and her family for their support and understanding regarding the writing of this article.

References

Footnotes

  • Competing interests None.

  • Patient consent Parental/guardian consent obtained.

  • Provenance and peer review Commissioned; externally peer reviewed.