Brew, Bruce --- "One-hit wonder? Neurological conditions that can follow nervous system damage" [2018] PrecedentAULA 22; (2018) 145 Precedent 30

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ONE-HIT WONDER?

NEUROLOGICAL CONDITIONS THAT CAN FOLLOW NERVOUS SYSTEM DAMAGE

By Professor Bruce Brew

INTRODUCTION

Most people consider that when the nervous system is injured, the consequences of that injury are immediately apparent at that time. There is ‘one hit’. Generally speaking, other conditions are no more likely to occur. This assumption is now proving to be incorrect, at least in relation to the brain and the spinal cord. This article sets out the consequences of brain and spinal cord injury that can occur later, and the potential mechanisms and methods by which the risk for developing these consequences can be identified.

These issues are clearly important from a legal perspective. The potential for the later development of these disorders has to be considered when assessing a client’s current condition – not only because of the possibility of additional disability in general but also, more specifically, impairment of the client’s cognitive capacity.

DEFINITIONS

Virtually any type of injury to the brain and to a lesser extent the spinal cord (trauma, infection, malignancy and metabolic aberrations) can be associated with the later development of other conditions. For the purpose of this article I have defined ‘later’ as occurring approximately a year or more after the initial injury and ‘conditions’ as clinical deficits that are persistently worse in either severity (for example, increased weakness in a previously weak limb) or distribution (for example, weakness in another limb). The ‘condition’ may have the same clinical features as those causing the original injury, or may be completely different with no apparent connection.

These definitions seem to fit the data on this topic as determined by the current published literature. The reason for defining ‘later’ as a year or more is to exclude injury-related complications (for example, blood electrolyte abnormalities) that are not uncommon in the weeks to months after a brain injury and which can worsen clinical deficits but only in the short term. The reason for including the criterion of ‘persistently worse’ is to exclude occasions where clinical deficits are unmasked or worsened in the short term by an intercurrent illness. Perhaps the best example of this is where a chest infection can lead to the exacerbation of deficits in a patient who had a stroke years previously. This has recently been termed ‘post-stroke recrudescence’,^[1] though experienced clinicians have long been aware of this.

WHAT TYPES OF BRAIN INJURY CAN BE ASSOCIATED WITH LATER CONDITIONS?

Some of these associations are well known and appreciated. Examples are the increased risk of epilepsy years after trauma to the brain. Others are less well known and sometimes controversial. An example is the association between brain trauma and multiple sclerosis, a long-running controversy with recent data adding fuel to the fire.^[2]

The well-known associations in more detail are as follows. Perhaps the best appreciated is the risk of developing epilepsy after traumatic brain injury (TBI). This varies widely in the literature from 2 per cent to 53 per cent depending on certain factors (vide infra). While the condition is well known, it is poorly appreciated that the risk extends not just for the first few years after the trauma. Indeed, the more severe the trauma, the greater time period over which that risk extends. The probability of developing unprovoked seizures five years after mild TBI was 0.7 per cent; after moderate injury 1.2 per cent; and 10 per cent after severe injury. Indeed, the cumulative probability of developing seizures within 30 years was 2.1 per cent, 4.2 per cent, and 16.7 per cent after mild, moderate and severe injury. However, accounting for other epilepsy risk factors results in no greater risk in mild injury than in the general population after five years.^[3]

Stroke is also associated with the later development of epilepsy. The pooled incidence of late stroke-related seizures based on 20 studies is 18 per 1,000 person-years (95 per cent confidence) even after 10 years.^[4] The seizures may be focal, generalised or both.

Stroke can also lead to dementia. About one-third of stroke survivors have a significant degree of cognitive impairment within the first months after the stroke. Indeed, approximately half of patients with a first-ever small stroke may have mild cognitive impairment. The extent to which this interferes with activities of daily living (the key criterion for classifying cognitive impairment as dementia) is often difficult to assess, given the effect of other stroke-related neurological deficits that can impair activities of daily living. By convention, the term ‘post-stroke dementia’ is reserved for deficits that are present six months after the event, but it should be noted that prospective studies show a linear increase of 1.7 and 3 per cent each year. This is in contrast to cognitive changes in the normal ageing population where a linear rate of change is not observed. It is also important to appreciate that post-stroke dementia is a subcategory of vascular cognitive impairment and vascular dementia, overlapping with post-stroke mood disorder. Vascular dementia usually encompasses multiple strokes although sometimes one or a few strokes in critical areas of the brain can cause dementia. Additionally, vascular dementia can occur because of damage to white matter of the brain even in the absence of strokes.^[5]

Polio can also be associated with new neurological deficits years after the original illness. Post-polio syndrome is thought to occur in 20 to 85 per cent of those affected by polio, depending on the stringency of the criteria used.^[6]

Meningitis, particularly bacterial, parasitic or fungal, can lead to cognitive impairment through hydrocephalus months to a year or so after the initial illness. The frequency with which this occurs varies widely and depends largely on the underlying organism responsible for the meningitis.

Encephalitis of any cause can lead to epilepsy with either focal or generalised seizures years after the illness. Again, the frequency with which this happens varies widely. Encephalitis secondary to herpes simplex can lead to further neurological deficits, including cognitive impairment, months to a year after the illness in approximately 20 per cent of patients. This is related to the development of antibodies that cause damage through an autoimmune mechanism. This may also occur after other viral encephalitides, although definitive data are awaited.^[7]

Epileptic seizures may also worsen over time despite the absence of any further causal agent. This tendency was originally encapsulated as ‘seizures beget seizures’ by Sir William Gowers over a century ago. However, it is not clear how often this happens, and indeed whether it happens at all as a general feature of epilepsy. Rossini et al^[8] have presented convincing evidence that at least in one specific type of epilepsy – focal cortical dysplasia – this is not the case. However, generalised seizures, especially in the context of status epilepticus, likely still remain associated with an increased risk of brain damage from the seizure which then can serve as an additional cause for further seizures, a phenomenon known as ‘kindling’.

There are some less well-known associations. TBI is associated with a variety of general neurological sequelae.^[9] Even patients with mild injury can have functional decline years after the event and have an increased mortality rate, although it is unclear whether this is directly causally related to the mild injury or an indirect association with the brain injury serving as a surrogate for a hazardous lifestyle. TBI is associated with an increased risk of Parkinson’s disease as well as dementia in general, especially Alzheimer’s disease and dementia with Lewy bodies. TBI is also associated with an increased risk of stroke some five years after the trauma. There are, however, the same caveats regarding whether the association is causal.

Lastly, TBI is increasingly recognised as leading to the condition known as ‘chronic traumatic encephalopathy’. This has recently been described in American football players who have had several episodes of concussion over their playing career.^[10] While much needs to be defined, it would seem that the condition is essentially a broadening of dementia pugilistica to include milder forms of cognitive impairment. ‘Dementia pugilistica’ is an old term to describe the development of dementia in boxers years after cessation of boxing. The frequency with which chronic traumatic encephalopathy occurs is currently a matter of heated debate and research.

WHAT ARE THE POTENTIAL MECHANISMS FOR SUCH LATE SEQUELAE?

The mechanisms underpinning these associations are only partly understood. While remodelling of brain connections after TBI or stroke may go awry,^[11] leading to increased expression of excitatory nerve pathways with subsequent seizures, the reasons for the delay of several years and the development in only some patients are unclear. TBI is known to be characterised by numerous pathological abnormalities such as diffuse axonal injury and blood–brain barrier disruption. These changes may facilitate the development of degenerative conditions such as dementia.^[12] Post-polio syndrome is thought to occur because of the overuse of unaffected motor units along with the effects of age-related decline and possibly the effect of residual fragments of the polio virus and chronic inflammation.^[13] However, a common theme in all these conditions is the compromise of the normal reserve in the central nervous system. Every organ in the human body is ‘built’ with a degree of redundancy; teleologically this would seem to enable it to withstand the vicissitudes of life. Less reserve would therefore facilitate the earlier development of conditions that may not otherwise have occurred for several years.

HOW CAN THE RISK OF SUCH SEQUELAE BE IDENTIFIED?

Methods to identify and quantify an increased risk of developing these conditions are inchoate. Nonetheless, some broad principles are emerging. Older age, pre-injury status (including comorbid disorders such as alcohol and substance use, the presence of silent strokes), severity of injury and emotional adjustment to the injury are all important for each of the aforementioned conditions. The relative contributions for each of these, however, still requires research. Additionally, there are disease-specific risk factors. Haemorrhagic subtype, and cortical involvement are important for the development of stroke-related seizures. Dominant cerebral hemisphere involvement by stroke is a risk factor for post-stroke dementia.

CONCLUSIONS

While it is relatively uncommon, injury to the brain or spinal cord can be associated with the later development of a number of both related and unrelated neurological conditions. Surprisingly, the interval can be of the order of years, in some cases. Further research is needed to understand who is at risk and how that risk can be minimised.

Professor Bruce Brew AM MBBS (Hons) DMedSci DSc FRACP FAAN is a Neurologist at St Vincent’s Hospital, Sydney and Director of the Peter Duncan Neuroscience Research Unit and Applied Neurosciences Program at the St Vincent’s Centre for Applied Medical Research.

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^[1] M A Topcuoglu, E Saka, S B Silverman et al, ‘Recrudescence of Deficits After Stroke: Clinical and Imaging Phenotype, Triggers, and Risk Factors’, JAMA Neurology, 74(9), 2017, 1048-55 <http://jamanetwork.com/journals/jamaneurology/fullarticle/2646625> .

^[2] S Montgomery, A Hyoshi, S Burkill, L Alfredsson, S Bahmanyar, T Olsson, ‘Concussion in adolescence and risk of multiple sclerosis’, Annals of Neurology, 82, 2017, 554-61.

^[3] L L Zimmermann, R Diaz-Arrastia, P M Vespa, ‘Seizures and the Role of Anticonvulsants After Traumatic Brain Injury’, Neurosurgery Clinics of North America, 27(4), 2016, 499-508.

^[4] E Ferlazzo, S Gasparini, E Beghi et al, 'Epilepsy in cerebrovascular diseases: Review of experimental and clinical data with meta-analysis of risk factors’, Epilepsia, 57(8), 2016,1205-14; J Z Wang, M V Vyas, G Saposnik, J G Burneo, ‘Incidence and management of seizures after ischemic stroke: Systematic review and meta-analysis’, Neurology, 89(12), 2017, 1220-8; A Pitkänen, R Roivainen, K Lukasiuk, ‘Development of epilepsy after ischaemic stroke’, The Lancet Neurology, 15(2), 2016,185-97.

^[5] M D Mijajlović, A Pavlović, M Brainin et al, ‘Post-stroke dementia – a comprehensive review’, BMC Medicine, 15(1), 2017, 1.

^[6] H Gonzalez, T Olsson, K Borg, ‘Management of post-polio syndrome’, The Lancet Neurology, 9(6), 2010, 634-42.

^[7] H Prüss, ‘Postviral autoimmune encephalitis: manifestations in children and adults’, Current Opinion in Neurology, 30(3), 2017, 327-33.

^[8] L Rossini, R Garbelli, V Gnatkovsky et al, ‘Seizure activity per se does not induce tissue damage markers in human neocortical focal epilepsy’, Annals of Neurology, 82, 2017, 331-41.

^[9] L Wilson, W Stewart, K Dams-O'Connor, R Diaz-Arrastia, L Horton, D K Menon, S Polinder, ‘The chronic and evolving neurological consequences of traumatic brain injury’, The Lancet Neurology, 10, 2017, 813-25.

^[10] J Mez, D H Danesgvar, P T Kiernan et al, ‘Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football’, JAMA Neurology, 318, 2017, 360-70.

^[11] See Ferlazzo et al at above note 4; Wang et al at above note 4; and Mez et al at above note 10.

^[12] See above note 9.

^[13] See above note 6.