Complications associated with intrathecal drug delivery in a paediatric patient with Niemann-Pick type C

Abstract

We report on a male subject with a diagnosis of Niemann-Pick type C (NPC). He received an experimental medicinal product intrathecally initially via lumbar puncture (LP) and eventually via intrathecal drug delivery device. Shortly after implantation, the device catheter migrated outside of the intrathecal space and coiled subcutaneously. The treatment continued via LP after removal of the device. A subdural haematoma developed after repeated LPs. It was surgically evacuated and the patient recovered with sequelae. Surgically implanted drug delivery devices are designed to bypass the blood–brain barrier and deliver a medicinal product directly into the cerebrospinal fluid circulation. Their use has extended into the field of neurodegenerative disorders. Significant adverse events can occur at any given time after implantation including neurological injury, dislodgement or displacement of any of its components, infection and drug-related complications; all can significantly affect the quality of life of patients. Repeated LPs also carry significant risk.

Background

Niemann-Pick type C (NPC) is an autosomal recessive disorder caused by mutations in the NPC1 gene or, less frequently, the NPC2 gene (OMIM#257220; OMIM#607625). It results in an abnormal endosomal-lysosomal trafficking with the subsequent accumulation of cholesterol intracellularly and secondary storage of other complex molecules that result in a progressive neurodegenerative phenotype.¹

NPC is a rare disease with an estimate incidence of 1 in 100 000–150 000 live births.^{1 2} The clinical manifestations range from a fatal antenatal disorder to an adult onset chronic neurodegenerative disease. Hypotonia and delay in developmental motor milestones characterise the neurological manifestation of NPC in early infancy. Hepatosplenomegaly and/or a neonatal prolonged jaundice are almost invariably noted. The late-infantile and juvenile forms are characterised by clumsiness, ataxia and fine motor skills impairment accompanied by dysarthria and hepatosplenomegaly. Gelastic cataplexy, sensory deafness and vertical supranuclear gaze palsy may also be present.^1–3

There is currently no disease-specific curative therapy available. The treatment is based on a multidisciplinary approach for symptom management focusing on inhibition of substrate accumulation, increase of defective protein functionality and reduction of inflammatory and oxidative stress sequelae.¹

Recent evidence has shown the potential of 2-hydroxypropyl-beta-cyclodextrine (2HP-β-CD) to delay clinical onset and extend lifespan. It reduces neuronal accumulation of unesterified cholesterol and glycosphyngolipids by forming inclusion complexes that facilitate the mobilisation of these compounds. However, it has a low capacity to cross the blood–brain barrier (BBB), requiring direct intrathecal injection every other week.⁴

Surgically implanted drug delivery devices are designed to bypass the BBB and deliver a medicinal product directly into the cerebrospinal fluid circulation and/or into the brain parenchyma. In this paper, we describe a case of an NPC subject treated with intrathecal 2HP-β-CD, we discuss the complications of current available options for intrathecal drug delivery and look into future alternative approaches to bypass the BBB.

Case presentation

We report on a male subject diagnosed with NPC (compound heterozygous for the NPC1 c.3019C>G p.(Pro1007Ala) pathogenic variant and the likely pathogenic c.2827A>G p.(Ile943Val) variant). He developed classical symptoms of NPC including dysarthria, short memory loss, ataxia and lack of coordination and balance. He did not develop seizure activity during this period.

At age 15, he was enrolled in a clinical trial that evaluated the effect of 2HP-β-CD in subjects with neurological manifestations of NPC. The medicinal product was initially delivered via lumbar puncture (LP) under sedation every 2 weeks using a 22G Quincke-type needle. On numerous occasions, the patient complained of headaches, back pain and leg pain within the first 24 hours after the procedure. These symptoms were never severe and were managed at home with oral analgesia (paracetamol, ibuprofen).

Four months after starting this experimental treatment, the subject had a spinal intrathecal access port device (B. Braun Celsite Spinal Access Port System) implanted to provide an alternative to administration via repeated LP. The procedure was uncomplicated. The port was placed subcutaneously in the right mid-axillary line and the catheter was inserted through the L4-L5 interspinous space using a Tuohy needle. The tip was positioned under fluoroscopic control. The caudal end of the catheter was secured to the lumbo-dorsal fascia with the clamps provided and non-absorbable sutures.

No immediate complications were noticed. However, 4 days after implantation, the patient presented with acute pain on the reservoir pocket site after a sudden movement. The site became swollen and bruised. The day after this episode, he complained of headache and back pain, and it was also noted that the lumbar catheter insertion site had become swollen and painful. Imaging studies revealed that the catheter had migrated outside of the intrathecal space (figure 1). The port and catheter were surgically removed and the patient subsequently continued to receive the experimental treatment via LP. Previously described symptoms related to NPC persisted, ptosis and vertical supranuclear gaze palsy became more evident, although his gait became more ataxic, he was still able to walk independently.

Figure 1.

X-ray of lumbar spine. The catheter has migrated outside of the intrathecal space and is coiled in the subcutaneous space.

Ten months later, the patient experienced intense pain in his back, legs and hips after one of the regular treatment doses via LP. He became dizzy and developed an unusual behaviour characterised by confusion and polydipsia during the following approximately 12 hours. He had a prolonged tonic–clonic seizure while in the hospital; as initial measures to control the seizure failed, he required intubation and sedation. Blood results showed severe hyponatraemia (117 mEq/L). He was kept sedated and ventilated for 24 hours; no further seizures were reported after correction of his plasma sodium. On reversal of his sedation, he was noted to have severe lower limb weakness and urinary incontinence. MRI of the spine showed a subdural haematoma extending from L1 to S2 with significant cauda equina compression (figure 2). This was evacuated through a lumbar laminoplasty and durotomy.

Figure 2.

MRI of spine lumbar sacral with contrast. T1 hyperintense haematoma is seen in relation to the thecal sac (L1-S2), most of it subdural and intrathecal with possible small epidural component. Significant cauda equina root compression.

Outcome and follow-up

The patient recovered with sequelae (lower limb paraesthesia, urinary and faecal incontinence). Due to the various complications arising from intrathecal administration of the experimental treatment, he was subsequently withdrawn from the clinical trial and continues under multidisciplinary care.

Discussion

Intrathecal drug delivery devices are used primarily for the management of pain (malignant and non-malignant) and spasticity. However, in recent years, they have been adapted for experimental enzyme replacement in neurometabolic disorders such as NPC, metachromatic leukodystrophy and mucopolysaccharidosis types 1 and 2.^5–7

These devices allow a therapeutic substance to bypass the BBB by injecting it directly into the cerebrospinal fluid circulation. However, as with any invasive procedure, there is risk of complications that may occur at any time after implantation (table 1). Infection of the surgical site seems to be the most frequent complication overall.^8–12

Table 1.

Classification of intrathecal drug delivery device-related complications

Classification	Type of complication	Characteristics
Surgical	Bleeding	Intraoperative Postoperative
	Cerebrospinal fluid (CSF) leakage	Dural tear Peri-catheter
	Spinal cord or nerve injury	Temporary or permanent
Equipment	Pump/Reservoir	Medicinal product leak Mechanical or software malfunction Iatrogenic damage
	Catheter	Obstruction/Occlusion Displacement/Migration Disconnection Kinking/Breakage/Disruption
Patient specific	Infection	Catheter implantation site Pump/Reservoir pocket Meningitis
	Wound seroma	Back wound Pump/Reservoir pocket
	Granuloma	Proximal to catheter tip
Medication specific	Adverse reactions	Anaphylaxis Inflammatory response
	Overdose or insufficient dose	Pump/Reservoir malfunction
Operator specific	Inability to access the device	Delivery of the medicinal product outside of the reservoir (subcutaneous space)

In this case, we describe two serious complications related to intrathecal drug delivery: catheter migration and subdural haematoma.

Catheter migration

There is limited information in the literature on the prevalence of catheter-related complications in the paediatric population. In a case series of children with cerebral palsy with an intrathecal baclofen pump, the rate of complications requiring surgical management was 31%¹³; however, this rate is related to all complications rather than to catheter migration alone. A similar paediatric population was analysed by Motta et al where 15.1% had catheter issues, occurring most frequently during the first year after implantation.¹⁴ Catheter-related complications are also the most common indication for surgical revision in adults,^{9 15} with a rate varying between 10% and 45%.¹⁶

In our patient, the device was inserted and anchored in the standard recommended technique. He developed intense pain where the subcutaneous reservoir had been implanted after a sudden movement (standing up and stretching his arms above his head). It is difficult to infer if this movement caused the catheter to come out of the intrathecal space or if it was product of friction between the fascia and the vertebral bodies over the few days after implantation. The sutured clamp that retained the catheter to the fascia had not dislodged, as can be appreciated in figure 1.

Subdural haematoma

Mild complications after LP are not unusual (~30% prevalence) in both adult and paediatric populations. Back pain and headache are the most common. Serious complications such as subdural haematoma are very rare (prevalence 0.01%) and are typically associated with abnormal coagulation. Needle type and size are associated with mild complications (atraumatic small gauge needles carry a lower risk factor) but do not impact on the development of the more severe complications.¹⁷

Multiple attempts may cause swelling, bruising and scarring of the LP site and is another known risk factor for mild complications.¹⁷ In our case, the patient had recurrent LPs every other week for almost 2 years; he is thought to have had a total number of about 50 LPs. It is not clear from the current literature if this would have a cumulative risk for severe complications given that the pathophysiological mechanism for post-LP subdural haematoma is not fully understood. A small cohort of patients with SMA (spinal muscular atrophy) showed that repeated dosing via LP was ‘challenging’ for a large proportion of the subjects and more data are needed to compare efficacy with other delivery methods.¹⁸

To our knowledge, hyponatraemia as a complication of intrathecal delivery of 2HP-β-CD has not been described in the literature. It is likely that the neurotrauma was the cause of hyponatraemia probably by inappropriate secretion of antidiuretic hormone or cerebral salt wasting.¹⁹ However, the patient was not treated in our centre during the acute phase and the exact cause could not be confirmed. There was no recurrence of hyponatraemia after being corrected.

Future of intrathecal therapies

There has been significant increase in the development of drugs and novel therapies for rare diseases, but unfortunately, the development of better devices (including intrathecal drug delivery devices) has not followed in parallel to that growth.²⁰ On the other hand, intrathecal delivery devices might become obsolete in the future with the development of new drug delivery technologies that do not require invasive procedures and manage to penetrate the BBB.²¹

Receptor-mediated transporters use a ‘Trojan horse’ approach where the drug is conjugated to ligands that bound to known receptors (insulin, transferrin) and ferry the active components into the brain parenchyma. Carrier transporters are nanoscale vesicles that encapsulate the drug and penetrate the BBB by active or passive transport routes. Both approaches are promising but carry their own risks (toxicity), and more experience in humans is needed.²¹

Learning points.

• Adapting intrathecal drug delivery systems for the treatment of neurometabolic disorders has generated more opportunities for treating previously untreatable conditions.

• Intrathecal drug delivery has a risk of complications that can significantly affect the quality of life of these patients, even when the appropriate techniques are used.

• There is a need for less invasive and more efficient drug delivery methods that can mitigate the severe complications of the more invasive currently available options.