Journal Reviews

Posted in Journal Reviews on 3rd Apr 2014

Accelerating the diagnostic odyssey of ataxia?

Reviewer: Dr Gemma Cummins, Van Geest Centre for Brain Repair, Cambridge University, UK.

Gene discovery is a crucial first step in the development of targeted therapeutics for many rare ataxia disorders, as it allows us to study the function of the protein or RNA mediating the disease process. Although some would lament that the rate of development of these new therapies has been disappointingly slow in comparison to the rate of gene discovery, these advancements have allowed thousands of patients a definitive diagnosis, enabling genetic counselling and better management. Next generation sequencing (NGS) is a new method of rapidly determining the nucleotide sequence of a genome at low cost and with impressive accuracy. It is hoped that it will further accelerate the speed at which patients with neurogenetic diseases are diagnosed, and ultimately stimulate further research into the neurobiology of these conditions.

Németh et al recently published an article in ‘Brain’ whereby they utilised this advanced technique to see if they could elucidate a molecular diagnosis for 50 patients in the UK with ‘difficult to diagnose’ ataxias. These patients had already had extensive negative biochemical tests, and had tested negative for Friedrich’s ataxia, the common SCA genes and frequently several other genes initially screened for by their neurologists. They performed targeted capture on 58 genes already known to be associated with human ataxia, and an additional 59 genes considered to be good candidates from functional studies or animal data.

In total, they succeeded in diagnosing 9 out the 50 patients using NGS. In the cases where they made an eventual diagnosis, the delay was 3-35 years (mean 18.1 years) from disease onset. The best detection rate was in those with an adolescent onset and a family history (75%). The results of this pilot study demonstrate that NGS can improve diagnostic accuracy in cohorts of very challenging heterogenous patients. It is also cost effective: currently a single gene test using Sanger sequencing costs £700 as compared to a cost of £1000 to test for 50 genes with the Ataxia NGS panel. The authors discuss why even after NGS screening, some patients still did not have a molecular diagnosis. It is possible that some patients in this phenotypically diverse group may have had mitochondrial disorders (the mitochondrial genome is not included in the capture), neurodegenerative metabolic conditions or hereditary spastic paraparesis. It is also possible that some truly pathogenic mutations were classified as benign. Additionally, all sequencing technologies are limited in their ability to detect copy number variations such as large deletions or insertions. In future, it is likely that refined bioinformatics programmes, and whole genome sequencing methods will increase the detection rate further.

Németh AH, Kwasniewska AC, Lise S et al. Next generation sequencing (NGS) for molecular diagnosis of neurological disorders using ataxias as a model. Brain. 2013 Oct;136: 3106-18.


 One More Time?

Reviewer: Lloyd Bradley, St Richard’s Hospital, Chichester, UK.

The general consensus around timing of rehabilitation following an acquired brain injury is that the earlier things start, the better the outcome. Less explicitly expressed is the assumption that patients will reach a plateau at which point the aims of rehabilitation move from an active goal-orientated process to a passive care model.

The way that inpatient units are set up and funded means that inpatient rehabilitation is seen as a discrete and time limited process that comes to a very definite stop when a certain level of functioning has been reached, or when there are no longer goals to achieve. This paper from Germany suggests that for individuals who have sustained a traumatic brain injury, late inpatient interval rehabilitation many months following original discharge from a healthcare setting may be beneficial. Ninety four patients with either traumatic or vascular injuries were involved in a longitudinal cohort study of the efficacy of a rehabilitation programme in the chronic phase following severe brain injury.

This programme consisted of 300 minutes of multi-disciplinary therapy time a day directed towards specific goals. The patient group are defined as “severely brain injured” and yet the inclusion criteria seem a little vague (a Barthel Index of <20!). The referral process into the programme is also not made explicit and given the importance of patient selection for inpatient rehabilitation, perhaps this needed to be made more obvious.

Outcome measures were the Functional Independence Measure (FIM), Barthel Index (BI) and the Coma Recovery Scale (CRS). Over half of the patient group had tracheostomies in situ and 15% were at a level compatible with a vegetative state. The main “goal” achieved for the patient group was decannulation although only 37% of patients’ admissions were rated as “successful” (most of these admissions achieving the goal of decannulation). There was little benefit seen for levels of awareness, communication and swallowing. Twelve patients admitted from nursing homes were able to be discharged back to their own homes after the intervention. It is interesting that the rate of change of the FIM was found to be greater (two points per month) in the late inpatient setting compared with the community (one point per month), but given the point change needed for a clinically relevant improvement is 27, this is obviously of doubtful relevance.

While there may be some merit in late interval inpatient rehabilitation, the ‘community’ setting to which these patients were discharged following their initial admission to rehabilitation is surely an important issue. If rehabilitation is seen as beginning and ending with inpatient units we may be missing an opportunity to facilitate greater gains after inpatient discharge by providing interventions and monitoring in the real world. Rehabilitation does not just happen in rehabilitation units.

Bender A, Bauch S, Grill E. Efficacy of a Post-Acute Interval Inpatient Neurorehabilitation Programme for Severe Brain Injury. Brain Injury. 2014;28(1):44-50.


Pregabalin vs Pramipexole for Restless Legs

Reviewer: Dr Gemma Cummins, Van Geest Centre for Brain Repair, Cambridge University, UK.

Restless legs syndrome can significantly impact on patients’ quality of life and untreated it can lead to considerable fatigue and daytime somnolence. The mainstay of treatment for the condition currently is dopamine agonists, but they have the potential to cause iatrogenic worsening (augmentation) of RLS with long term treatment. Allen’s team at the Johns Hopkins University recently published a double-blind RCT in the NEJM which suggests pregabalin, an alpha-2-delta ligand, may be a viable alternative treatment.

A total of 719 participants with moderate to severe RLS were assigned to receive daily either 300mg of pregabalin, 0.25mg of pramipexole, 0.5mg of pramipexole or a placebo tablet. After 12 weeks of treatment, patients taking pregabalin reported a significantly greater improvement in their symptoms compared with those taking placebo (71% versus 47%), and pregabalin led to improvements similar to those assigned to the higher dose of pramipexole. Furthermore, after 52 weeks of treatment, fewer patients on pregabalin experienced a worsening of their condition, as compared to those taking mirapexin (2% versus nearly 8%).

Regarding side effects, there were six cases of suicidal ideation in the group receiving pregabalin, and five in the group receiving pramipexole. This trial provides compelling evidence for the efficacy of pregabalin in treating this common and distressing condition. It also raises a number of other interesting issues regarding the pathogenesis of RLS. It implicates a role for non-dopaminergic drugs in the treatment of the disease, thus suggesting a role of non-dopaminergic pathways in the poorly understood aetiopathogenesis. It also indicates that drugs besides dopamine agonists can lead to augmentation (albeit to a lesser extent), which has been noted previously with the drug tramadol. The jury is still undecided as to whether augmentation is an effect of medications, a process intrinsic to RLS or related to patient characteristics.

Chokroverty S. Therapeutic Dilemma for Restless Legs Syndrome. N Engl J Med 2014; 370:667-.8 Comparison of pregabalin with pramipexole for restless legs syndrome. Allen RP, Chen C, Garcia-Borreguero D. N Engl J Med. 2014 Feb 13;370(7):621-31.


Sleep detoxifies the brain

Reviewer: Jemeen Sreedharan, Dept of Neurobiology/ Neurology, University of Massachusetts Medical School, Worcester, USA.

Why do we sleep? It clearly has restorative properties in the broadest sense and it is thought to be important for memory consolidation. Forced sleep deprivation in animal models can kill. Another reason for sleep could be to prevent the build up of toxic moieties. Sleep deprived mice, for example, demonstrate a build up of amyloid beta, suggesting an intriguing link between Alzheimer’s risk and sleep. A series of mouse studies from the Nedergard lab provide further evidence in support of this link.

Nedergard’s lab showed last year that the mouse brain possesses something akin to a lymphatic system (Iliff 2012). Subarachnoid CSF enters the brain through channels around the outside of penetrating arteries. This paravascular space (the Virchow Robin space) is bounded on one side by the artery wall and on the other by astrocytic end feet (hence the phrase ‘glymphatic’ system). Aquaporin 4 water channels are concentrated at these end feet and are essential for fluid transfer. The passage of CSF appears to be one way: CSF flows from the subarachnoid compartment into the brain interstitium along para-arterial glymphatics, while brain interstitial fluid escapes along paravenular glymphatics into the ventricular system. They went on to show that amyloid beta protein is flushed out of the brain through the glymphatic system, the ventricles thus functioning as a latrine.

This year the same lab show that sleep profoundly increases the brain’s toileting capacity. Xie et al infused fluorescent dyes into the CSF of mice and performed live imaging through cranial windows. They directly observed the movement of the dyes through the cortex of the brain while the animals were awake, asleep or under anaesthetic (these various states were confirmed using electrocorticography and EMG). Being asleep was associated with a dramatic increase in tracer movement through the cortex, because of a ~60% increase in the volume of the interstitial space. Although the mechanism of this increased capacitance is unclear (could it be due to neuronal and glial shrinkage?) Xie et al hypothesised that noradrenaline (NA), which is important for arousal, may be involved. Indeed, when they applied NA antagonists the interstitial volume increased.

This evidence suggests that sleep opens up brain extracellular spaces, allowing toxic substances that have accumulated in the brain to be efficiently flushed out into the ventricles. One broad implication of this is that sleep deprivation could increase one’s risk of Alzheimer’s disease. Indeed, Alzheimer’s patients often have sleep disturbance, though how much of this is cause and how much the effect of neurodegeneration is not clear. For a detailed and incisive account of the ‘hypnic hypothesis’ of Alzheimer’s disease essential bedtime reading comes in the form of a recent review by Clark and Warren (2013). Sweet dreams.

Iliff JJ, Wang M, Liao Y et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012 Aug 15;4(147):147. 
Xie L, Kang H, Xu Q et al. Sleep drives metabolite clearance from the adult brain. Science. 2013 Oct 18; 342:373-7.
Clark CN, Warren JD. A hypnic hypothesis of Alzheimer’s disease. Neurodegener  Dis. 2013; 12:165-76.

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