Fits, feet and HIV: lessons from a case of coexisting epilepsy and neuropathy in a patient with perinatally acquired HIV-1 infection

Abstract

An 18-year-old black African man with well-controlled perinatally acquired HIV-1 was diagnosed in late adolescence with the unrelated diagnoses of Charcot-Marie-Tooth type 1A (CMT1A), epilepsy due to polymicrogyria and subsequently developed severe depression. The CMT1A diagnosis occurred after transfer of care from a local paediatric HIV service to a tertiary paediatric referral centre and was precipitated by recognition of a history and neurological signs not typically associated with perinatal HIV. The case resulted in the establishment of a quarterly combined paediatric HIV and paediatric neurology multidisciplinary team clinic to assess children and adolescents living with HIV with neurological symptoms.

Background

Complex chronic underlying multisystem diseases such as HIV can exert a strong framing effect which impacts on how new information is perceived and may make us vulnerable to inattentional blindness. The establishment of cross-specialty multidisciplinary teams (MDTs) for rare diseases of childhood has the potential to improve diagnostic yield, patient pathways and provide unique training opportunities. Rare diseases may, rarely, coexist and present diagnostic challenges for children and adolescents in long-term follow-up.

Case presentation

An 18-year-old black African man born in the UK was diagnosed with perinatally acquired HIV-1 (PaHIV) infection aged 18 months on family screening. Aged 5, following an episode of chickenpox with secondary bacterial infection, he was started on antiretroviral therapy (ART) with abacavir, lamivudine and Kaletra (lopinavir coformulated with ritonavir), nadir CD4 393 cells/µL. He achieved and maintained excellent virological control, (plasma HIV PCR <50 copies/mL) with immune reconstitution to CD4 count >500 cells/µL and when 12 years, therapy was simplified to a once daily regimen of darunavir, ritonavir and Kivexa (coformulated abacavir with lamivudine). He remained well and attended mainstream school. Following closure of his local paediatric HIV service, his care transferred to a tertiary paediatric HIV referral centre at the age of 15. Around that time, he developed tonic–clonic seizures, generalised in onset, which self-terminated within a few minutes. His CD4 count was 1087 cells/µL, plasma and CSF HIV viral loads <20 c/mL, and an initial cranial CT scan was reported as normal. After his third seizure, he was started on levetiracetam and a subsequent cranial MRI scan (figures 1–3) showed evidence of a disorder of neuronal migration with subependymal heterotopia adjacent to the right lateral ventricle and a small area of polymicrogyria in the right parietal cortex.

Figure 1.

Axial T2 showing a subependymal heterotopic nodule along the Right lateral ventricle, isointense with grey matter and in keeping with subependymal heterotopic grey matter.

Figure 2.

Coronal T1 showing a subependymal heterotopic nodule along the Right lateral ventricle, isointense with grey matter and in keeping with subependymal heterotopic grey matter.

Figure 3.

Right Medial Frontal polymicrogyria.

During his initial paediatric HIV review, he mentioned he was not keen on sport, had never learnt to ride a bike without stabilisers, disliked walking barefoot, tired easily and had had bilateral foot surgery for hammer toes 1 year previously. On clinical examination, he rose from the floor through half kneeling using his upper limbs and furniture for assistance, struggled to hop and could not heel-toe walk. He had muscle wasting giving rise to a ‘stork leg’ appearance, with evidence of both motor and sensory impairment in his lower legs and weakness in his upper limbs.

Investigations

When reviewed in paediatric neurology, a clinical working diagnosis of hereditary motor and sensory neuropathy type 1 was made, confirmed as Charcot-Marie-Tooth type 1A (CMT1A) with a heterozygous chromosome 17p11.2 duplication and nerve conduction studies showing a severe symmetrical length-dependent sensorimotor demyelinating peripheral neuropathy, typical of CMT1.

Cognitive assessment using the Wechsler Intelligence Scale for Children UK Fourth edition showed an overall IQ 94 with reduced processing speed due to fine motor difficulty rather than cognitive processing speed weakness.

Treatment

The diagnosis was discussed with the patient and his mother. Referrals were made to: physiotherapy, orthotics, the CMT service at National Neurology Hospital, Queens Square, London and information given regarding the support group CMT UK (http://cmt.org.uk/). His father also had a history of bilateral foot surgery but failed to attend family screening appointments.

Outcome and follow-up

Four months after being told of his neurological diagnoses, his mother contacted the HIV service to report that her son had had a sudden change in mood, was not attending college, refusing to leave his room or talk to anyone. He remained adherent to medication, HIV <20 copies/mL, CD4 count 406 cells/µL and seizure free. Despite home visits from clinical nurse specialists, psychologists and a Child and Adolescent Mental Health Service referral, his mood deteriorated and he was admitted to an adolescent mental health unit for 6 weeks with a diagnosis of catatonic depression. His change in mood was not attributed to levetiracetam due to the 1-year delay between initiating treatment and onset of his affective symptoms. No organic cause was identified. He started escitalopram while continuing darunavir, ritonavir, Kivexa and levetiracetam with a slow improvement in mood and returned home.

Discussion

This young man with well-controlled PaHIV-1 infection presents in mid-adolescence with two further unrelated diagnoses: epilepsy secondary to neuronal migration disorder and a genetic cause for his weakness, that is, CMT1A and subsequently a diagnosis of severe depression. Patients with complex chronic diseases can have additional unrelated pathology that may go unnoticed, or be wrongly attributed to the already known diagnosis. This can contribute to diagnostic delay.

Neurological disease in children with perinatal HIV is often a result of HIV encephalopathy of infancy characterised by acquired microcephaly, delay or loss of motor, cognitive and linguistic milestones and pyramidal motor tract deficiencies.¹ Prior to combination ART, encephalopathy affected up to a fifth of children living with HIV; typically presenting in the first year of life, associated with rapid progression of HIV disease with cranial imaging showing cerebral atrophy and basal ganglia calcification. While suppressive ART halts progression of encephalopathy, frequently hypertonic diplegia and/or cognitive deficits persist for life.¹ In this case, there was no evidence of cerebral atrophy or cognitive delay and his lower limb neurology was inconsistent with pyramidal deficits, but in keeping with peripheral neuropathy. Unsuppressed HIV and or ART, particularly the older nucleoside analogues such as zidovudine and stavudine, can cause peripheral neuropathy. However, the patient had been virologically suppressed for more than a decade and had received nucleoside analogues abacavir and lamivudine, both of which are considered to be non-neurotoxic drugs.²

CMT is a demyelinating peripheral neuropathy characterised by distal muscle weakness, atrophy and sensory loss, frequently associated with foot deformity and foot drop,³ and affects approximately 10–80 per 100 000 individuals worldwide and 12 per 100 000 individuals in England.⁴ Individuals usually develop symptoms between 5 and 25 years. The subtype CMT1A is relatively benign with a slow progression, no reduction in predicted life span and fewer than 5% of individuals become wheelchair dependent. Autosomal dominant inheritance has implications for screening other family members and in preconception counselling. HIV and CMT coexistence is known, however, these instances appear rare with a hypothesised mechanism associated with either specific types of HIV drug therapy⁵ or recent HIV infection.⁶

While polymicrogyria is associated with 22q11.2 deletion syndrome, the patient was not investigated for this. He did not have other features to suggest 22q11.2 deletion syndrome or features of other genetic syndromes. After extensive MDT discussion and MRI investigation, it was felt that the polymicrogyria could be due to a perinatally acquired infection or related to the PMP22 duplication. Cytomegalovirus and other congenital infections are known to cause polymicrogyria.^{7 8} A woman living with untreated HIV infection, as the patient’s mother was during her pregnancy, is more susceptible to newly acquiring CMV infection or reactivation of a latent infection.

Opportunities were potentially missed to make an earlier diagnosis of CMT, which could have delayed the initiation of orthotic and physiotherapy services and additional support for fine motor skills in education. This case highlights the advantages of tertiary services where clinicians see a large number of children with rare chronic diseases within an MDT and have the advantage of being more likely to recognise patterns inconsistent with the primary diagnosis. The CMT1A was quickly picked up following transfer to tertiary services and the case resulted in the establishment of a quarterly combined paediatric HIV and paediatric neurology MDT clinic to assess children and adolescents living with HIV with neurological symptoms.⁹

The psychological impact of two additional independent chronic diseases cannot be underestimated, particularly occurring during mid adolescence. Preadolescents are usually cognitively capable of understanding their health condition, but better able than adolescents to accept it as part of their status quo. Within HIV services, clinicians aim for children to fully understand their HIV diagnosis between 8 and 11 years of age, in recognition of the difficulty in adjustment if naming is delayed into teenage years.¹⁰

Learning points.

• Complex multisystem conditions like HIV, cystic fibrosis or the consequences of severe prematurity exert a strong framing effect when forming a diagnosis.

• ‘Framing effects’ describe how the context surrounding information impacts on how new information is perceived and may make us vulnerable to inattentional blindness.

• Maintaining an open approach to evaluation of new symptoms in children and adolescents with chronic diseases is difficult and requires vigilance.

• The establishment of multidisciplinary team based across specialty services has the potential to improve diagnostic yield, patient pathways and provide unique learning opportunities to gain dedicated exposure to rare coexisting conditions.

• Rare diseases may, rarely, coexist and present diagnostic challenges for children and adolescents in long-term follow-up.