Refl ection and Reaction

www.thelancet.com/neurology Vol 9 August 2010 753

In this issue of The Lancet Neurology, Dalmau and colleagues1 show that the target antigen in patients with limbic encephalitis previously attributed to antibodies against voltage-gated potassium channels is in fact leucine-rich glioma-inactivated 1 (LGI1) protein, a neuronal secreted protein that might connect presynaptic and postsynaptic protein complexes for fi nely tuned synaptic transmission. These results

suggest that limbic encephalitis is a synaptopathy rather than a channelopathy.

In 1995, by use of a radioimmunoassay with 125I-α-dendrotoxin, antibodies against voltage-gated potassium channels were fi rst identifi ed in patients with neuro myotonia2 and were later also identifi ed in some cases of Morvan’s disease3 and in some patients with limbic encephalitis.4 These fi ndings completely changed

were enrolled within 72 h of ischaemic stroke in the Prevention Regimen for Eff ectively Avoiding Second Strokes (PRoFESS) study.5 Blood-pressure lowering seemed to be benefi cial according to a meta-regression analysis of the relation between blood-pressure reduction and outcomes in patients with acute stroke6 and is unlikely to produce major alterations in cerebral blood fl ow early after ischaemic stroke according to advanced imaging studies.7

Of course, controversy continues regarding the most appropriate management of raised blood pressure in the hyperacute (<6 h) phase after stroke, when potential treatment benefi ts are more likely to be realised. However, any such eff ects are probably more complex for ischaemic stroke, in which there is greater heterogeneity in pathophysiological mechanisms (eg, external or intracranial carotid stenosis or lacunar disease) and consistent U or J shaped associations between both baseline and follow-up blood-pressure levels and outcomes on epidemiological analyses compared with primary intracerebral haemorrhage. A randomised pilot trial suggested that early rapid blood-pressure lowering in intracerebral haemorrhage reduces haematoma expansion.8 The results of other clinical trials (the Scandinavian Candesartan Acute Stroke Trial [SCAST], the Effi cacy of Nitric Oxide in Stroke [ENOS] trial, the second Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial [INTERACT2], and the second Antihypertensive Treatment in Acute Cerebral Hemorrhage [ATACH2] trial) of blood-pressure reduction in acute stroke, both undiff erentiated and pathologically defi ned, are eagerly awaited.

In the meantime, COSSACS1 adds to an emerging consistent message: oral antihypertensive treatment

can be used safely in nearly all patients within the fi rst few days of mildly disabling or non-disabling stroke or transient ischaemic attack because of the modest size (about 6–12 mm Hg systolic) and speed (several hours) of the blood-pressure reduction. Prompt in-hospital initiation of such treatment should also maximise long-term effi cacy and adherence, but ideally effi cacy and adherence to this treatment regimen also require separate evaluation.

Craig Anderson Neurological and Mental Health Division, The George Institute for Global Health, University of Sydney and Royal Prince Alfred Hospital, Sydney, Australiacanderson@george.org.au

I am the principal investigator for the INTERACT2 study investigating early intensive blood-pressure lowering in acute intracerebral haemorrhage.

1 Robinson TG, Potter JF, Ford GA, et al, on behalf of the COSSACS Investigators. Eff ects of antihypertensive treatment after acute stroke in the Continue Or Stop post-Stroke Antihypertensives Collaborative Study (COSSACS): a prospective, randomised, open, blinded-endpoint trial. Lancet Neurol 2010; published online July 12. DOI:10.1016/S1474-4422(10)70163-0.

2 PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood pressure lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358: 1033–41.

3 Okumura K, Ohya Y, Maehara A, Wakugami K, Iseki K, Takishita S. Eff ects of blood pressure levels on case fatality after acute stroke. J Hypertens 2005; 23: 1217–23.

4 Waldstein SR, Lefk owitz DM, Siegel EL, et al. Reduced cerebral blood fl ow in older men with higher levels of blood pressure. J Hypertens 2010; 28: 993–98.

5 Bath PMW, Martin RH, Palesch Y, et al, for the PRoFESS Study Group. Eff ect of telmisartan on functional outcome, recurrence, and blood pressure in patients with acute mild ischemic stroke: a PRoFESS subgroup analysis. Stroke 2009; 40: 3541–46.

6 Geeganage CM, Bath PMW. Relationship between therapeutic changes in blood pressure and outcomes in acute stroke: a metaregression. Hypertension 2009; 54: 775–81.

7 Powers WJ, Videen TO, Diringer MN, Aiyagan VA, Zazulia AR. Autoregulation after ischaemic stroke. J Hypertens 2009; 27: 2218–22.

8 Anderson CS, Huang Y, Wang JG, et al; for the INTERACT investigators. Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. Lancet Neurol 2008; 7: 391–99.

Published OnlineJune 28, 2010DOI:10.1016/S1474-4422(10)70162-9

See Articles page 776

Is autoimmune limbic encephalitis a channelopathy?

Refl ection and Reaction

754 www.thelancet.com/neurology Vol 9 August 2010

our under standing of limbic encephalitis, previously thought to be a rare paraneoplastic neurological syndrome with a poor outcome and mainly associated with anti-Hu antibodies, anti-Ma2 antibodies, or anti-CV2/CRMP5 antibodies.5

Antibodies against voltage-gated potassium channels defi ned a distinct type of limbic encephalitis: only 10–33% of cases with these antibodies were paraneoplastic, and immunomodulatory treatments (eg, corticosteroids, plasma exchange, or intravenous immunoglobulin) improved neurological symptoms in about 90% of these patients.4 More patients with limbic encephalitis had antibodies against voltage-gated potassium channels than had anti-Hu antibodies, anti-Ma2 antibodies, or anti-CV2/CRMP5 antibodies.6 Importantly, there was an inverse association between titres of antibodies against voltage-gated potassium channels and neuropsychological improvement, suggesting a direct pathogenic role of the autoantibodies.4 These fi ndings led to the classifi cation of limbic encephalitis into two subtypes according to the autoantibodies associated with the disorder:7 the subtype with autoantibodies directed against intracellular antigens—always paraneoplastic, and with a poor prognosis—and the other subtype with autoantibodies directed against neuronal surface antigens—more common and with a better prognosis.

Recent descriptions of limbic encephalitis with antibodies against NMDA receptors,8 antibodies against the glutamate receptor 1 (GluR1) and GluR2 subunits of

the AMPA receptor,9 or antibodies against the B1 subunit of the GABAB receptor confi rmed this classifi cation of limbic encephalitis.6 All these autoantibodies directed against neuronal receptors substantially decreased the number of recognised receptors at the neuronal surface when added to cultures of neurons,6,8,9 suggesting a direct eff ect of these antibodies on receptor expression at the synapses and a role on neurological symptoms. However, antibodies against voltage-gated potassium channels were also found in a broad spectrum of immunological disorders and therefore these antibodies probably did not have a direct role in all these syndromes.

Many groups have tried, without success, to detect the autoantigen in patients with limbic encephalitis by testing sera or CSF in cells transfected with the Kv1.1 subunit of the voltage-gated potassium channel, which was thought to be the antigen. The autoantibodies that were identifi ed by ¹²⁵I-α-dendrotoxin radioimmunoassay as antibodies against voltage-gated potassium channels were suspected to react against antigens that co-precipitate with potassium channels. Contactin-associated protein 2 (CASPR2), a protein member of the neurexin family, was identifi ed as a potential target in patients with Morvan’s syndrome;10 Dalmau and colleagues1 clearly showed that patients with limbic encephalitis, neuromyotonia, and Morvan’s syndrome have autoantibodies directed against diff erent targets.10 Antibodies against CASPR2 are not specifi c to Morvan’s syndrome and were also found in 3% of patients with neuromyotonia and in 2% of patients with limbic encephalitis, but anti-LGI1 antibodies were only associated with limbic encephalitis.1 The main targets associated with neuromyotonia and with Morvan’s syndrome might also co-precipitate with potassium channels and could be described in the coming months.

The identifi cation of LGI1 as the main target of antibodies in patients with limbic encephalitis has many consequences for the understanding of the mechanisms that cause the main symptoms in this disease—limbic encephalitis, epilepsy, and delusions. LGI1 is probably a key protein of synaptic organisation and thus the understanding of other neurological disorders might also improve because of these fi ndings. LGI1 is a secreted protein that may function as a ligand to connect presynaptic disintegrin and metalloproteinase domain-containing protein 23 (ADAM23) with postsynaptic ADAM22 proteins; this

BSIP

VEM

/Scie

nce

Phot

o Li

brar

y

Coloured transmission electron micrograph of a synapse

Refl ection and Reaction

www.thelancet.com/neurology Vol 9 August 2010 755

Estimates suggest that 8% of all fi rst-ever strokes occur in Africa and that 5% of the 30 million stroke survivors worldwide live in Africa.1 The prevalence of stroke might increase in the future because of changes in exposure to major stroke risk factors and improved prevention and control of infectious diseases. A paucity of data from stroke studies in Africa2 severely limits our understanding of the burden of stroke in Africa. High-quality data on stroke incidence is important to identify the stroke occurrence in a population. Thorough case ascertainment using overlapping case identifi cation methods, a well defi ned source population (denominator), complete identifi cation of fatal and non-fatal events, and patients who are hospitalised or managed elsewhere are some of the challenges when doing a so-called ideal stroke incidence study. Even in countries where many epidemiological studies have

been done, few studies meet all the requirements for an ideal stroke incidence study. The challenges are even greater in many low-income and middle-income countries. Systems for medically certifi ed causes of death are available for less than one third of the 57 million deaths per year worldwide, and these systems are mainly available in high-income countries. In addition, in low-income and middle-income countries, large and variable numbers of patients with stroke are cared for in the community without contact with established health facilities.

In this issue of The Lancet Neurology, Walker and colleagues3 report on stroke incidence in rural and urban Tanzania by recording incident strokes in two well defi ned demographic surveillance sites (DSS) over a 3-year period from June, 2003, to June, 2006. The rural Hai DSS included 159 814 people and the urban

Published OnlineJuly 6, 2010DOI:10.1016/S1474-4422(10)70161-7

See Articles page 786

Stroke incidence studies in Africa

interaction could result in a trans-synaptic complex including presynaptic Kv1.1 channels and postsynaptic AMPA receptor scaff olds.1 Future studies should aim to establish the frequency of antibodies against LGI1 and other components of the trans-synaptic LGI1 protein complex in epileptic disorders that are suspected to be autoimmune. Identifying the role of the trans-synaptic LGI1 protein complex in sleep disorders, insomnia, hypothalamic dysfunction, hyponatraemia, hypothermia, hypersalivation, diff use pain, and anorexia—all symptoms frequently observed in patients with limbic encephalitis4—might lead to interesting fi ndings.

In summary, the identifi cation of LGI1 as the main target in patients with limbic encephalitis with antibodies previously attributed to voltage-gated potassium channels will facilitate immunological diagnosis. These fi ndings should also lead to a better understanding of the underlying immunological mechanisms of limbic encephalitis, and animal models could be developed to test new treatment strategies. Finally, the trans-synaptic LGI1 protein complex might have a major role in epileptic seizures, mood disorders, or neuropsychological symptoms, such as memory disturbance, and thus studies on the role of LGI1 could lead to the identifi cation of new therapeutic

strategies to treat epilepsy, mood disorders, or even neurodegenerative diseases, such as Alzheimer’s disease.

Jérôme HonnoratService de Neurologie B, Hôpital Neurologique Pierre Wertheimer, 69677 Bron Cedex, Francejerome.honnorat@chu-lyon.fr

I have no confl icts of interest.

1 Lai M, Huijbers M, Lancaster E, et al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol 2010; published online June 28. DOI:10.1016/S1474-4422(10)70137-X.

2 Shillito P, Molenaar PC, Vincent A et al. Acquired neuromyotonia: evidence for autoantibodies directed against K+ channels of peripheral nerves. Ann Neurol 1995; 38: 714–22.

3 Barber PA, Anderson NE, Vincent A. Morvan’s syndrome associated with voltage-gated K+ channel antibodies. Neurology 2000; 54: 771–72.

4 Vincent A, Buckley C, Schott JM et al. Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 2004; 127: 701–12.

5 Honnorat J, Antoine JC. Paraneoplastic neurological syndromes. Orphanet J Rare Dis 2007; 2: 22.

6 Lancaster E, Lai M, Peng X, et al. Antibodies to the GABAB receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol 2010; 9: 67–76.

7 Graus F, Saiz A, Lai M, et al. Neuronal surface antigen antibodies in limbic encephalitis: clinical-immunologic associations. Neurology 2008; 71: 930–36.

8 Dalmau J, Gleichman Aj, Hughes Eg et al. Anti-NMDA-receptor encephalitis: case series and analysis of the eff ects of antibodies. Lancet Neurol 2008; 7: 1091–98.

9 Lai M, Hughes EG, Peng X, et al. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol 2009; 65: 424–34.

10 Vincent A. Antibodies to contactin-associated protein 2 (caspr2) in thymoma and Morvan’s syndrome. Annals Neurol 2009; 66 (suppl 1): S3.