Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated
1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome
and acquired neuromyotonia
Sarosh R. Irani, Sian Alexander, Patrick Waters, Kleopas A. Kleopa, Philippa Pettingill,
Luigi Zuliani, Elior Peles, Camilla Buckley, Bethan Lang and Angela Vincent
Antibodies that immunoprecipitate 125I-a-dendrotoxin-labelled voltage-gated potassium
channels extracted from mammalianbrain tissue have been identified in patients with
neuromyotonia, Morvan’s syndrome, limbic encephalitis and a few cases of adult-onset
epilepsy. These conditions often improve following immunomodulatory therapies. However,
the proportions of the different syndromes, the numbers with associated tumours
and the relationships with potassium channel subunit antibody specificities have
been unclear. We documented the clinical phenotype and tumour associations in 96
potassium channel antibody positive patients (titres 4400 pM). Five had thymomas
and one had an endometrial adenocarcinoma. To define the antibody specificities,
we looked for binding of serum antibodies and their effects on potassium channel
currents using human embryonic kidney cells expressing the potassium channel subunits.
Surprisingly, only three of the patients had antibodies directed against the potassium
channel subunits. By contrast, we found antibodies to three proteins that are complexed
with 125I-a-dendrotoxin-labelled potassium channels in brain extracts: (i) contactin-associated
protein-2 that is localized at the juxtaparanodes in myelinated axons; (ii) leucine-rich,
glioma inactivated 1 protein that is most strongly expressed in the hippocampus;
and (iii) Tag-1/contactin-2 that associates with contactin-associated protein-2.
Antibodies to Kv1 subunits were found in three sera, to contactin-associated protein-2
in 19 sera, to leucine-rich, glioma inactivated 1 protein in 55 sera and to contactin-2
in five sera, four of which were also positive for the other antibodies. The remaining
18 sera were negative for potassium channel subunits and associated proteins by
the methods employed. Of the 19 patients with contactin-associated protein-antibody-2,
10 had neuromyotonia or Morvan’s syndrome, compared with only 3 of the 55 leucine-rich,
glioma inactivated 1 protein-antibody positive patients (P50.0001), who predominantly
had limbic encephalitis. The responses to immunomodulatory therapies, defined by
changes in modified Rankin scores, were good except in the patients with tumours,
who all had contactin-associated-2 protein antibodies. This study confirms that
the majority of patients with high potassium channel antibodies have limbic encephalitis
without tumours. The identification of leucine-rich, glioma inactivated 1protein
and contactin-associated protein-2 as the major targets of potassium channel antibodies,
and their associations with different clinical features, begins to explain the diversity
of these syndromes; furthermore, detection of contactin-associated protein-2 antibodies
should help identify the risk of an underlying tumour and a poor prognosis in future
patients.
BRAIN 2010: 133; 2734–2748
http://brain.oxfordjournals.org/content/133/9/2734.full.pdf
The expanding clinical profile of anti-AMPA Receptor Encephalitis
F. Graus, A. Boronat, X. Xifró, M. Boix, V. Svigelj, A. García, A. Palomino, L. Sabater,
J. Alberch, and A. Saiz
Summary
Antibodies to the glutamate receptor 1 (GluR1) AND GluR2 subunits of the α-amino-3-hydroxy-5-methyl-4-isoxazoleprionic
acid (AMPA) receptor (AMPAR-ab) were recently described in 10 patients from a series
of 109 with limbic encephalitis (LE). Besides the hippocampus, GluR1/2 subunits
of AMPAR are also widely expressed in the cerebral cortex, basal ganglia, and cerebellum,
suggesting that the clinical presentation could also extend beyond the clinical
profile of LE. In this study, we analyzed the presence of AMPAR-ab in a consecutive
series of patients whose serum or CSF was sent to our laboratory for analysis of
antineuronal antibodies in the last 2 years.
NEUROLOGY. (2010) 74 (10) , 857-859
Is autoimmune limbic encephalitis a channelopathy?
Jérôme Honnorat
Summary
Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series
THE LANCET NEUROLOGY (2010) 9 (8) 776-785
Post-infectious encephalitis in adults: Diagnosis
and management
R. Sonneville, I. Klein, T. de Broucker, M. Wolff , BichateClaude, Henri Huchard,
Summary
Many important central nervous system (CNS) syndromes can develop following
microbial infections. The most severe forms of post-infectious encephalitis include acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis and Bickerstaff’s brainstem encephalitis. ADEM is an inflammatory demyelinating disorder of the CNS. It typically follows a minor infection with a 2e30 days latency period and is thought to be immune-mediated. It is clinically characterized by the acute onset of focal neurological signs and encephalopathy. Patients can require intensive care unit admission because of coma, seizures or tetraplegia. Cerebrospinal fluid analysis usually shows lymphocytic pleocytosis but, unlike viral or bacterial encephalitis, no evidence of direct CNS infection is found. There are no biologic markers of the disease and cerebral magnetic resonance imaging is essential to diagnosis, detecting diffuse or multifocal asymmetrical lesions throughout the white matter on T2- and FLAIR-weighted sequences. High-dose intravenous steroids are accepted as first-line therapy and beneficial effects of plasma exchanges and intravenous immunoglobulins have also been reported. Outcome of ADEM is usually favorable but recurrent or multiphasic forms have been described.
JOURNAL OF INFECTION (2009) 58, 321-328
Acute disseminated encephalomyelitis. A follow-up study of 40 adult patients
S. Schwartz, A.Mohr, M. Knauth, B. Wildmann, B. Storch-Hagenlocher
To describe the clinical, CSF, and radiologic findings and long term follow-up in
a cohort of patients with acute disseminated encephalomyelitis (ADEM), and to determine
possible prognostic factors for progression to MS.
NEUROLOGY 56 May (2 of 2 ) 2001
Limited chronic focal encephalitis
A. Gambardella MD, F. Andermann MD, S. Shorvon MD,
E. Le Piane MD and U. Aguglia MD.
Objective: To describe a more limited and less malignant form of Rasmussen
encephalitis (RE).
Methods: Three subjects (all women; 37, 31 and 32 years of age) developed
childhood or late onset chronic focal encephalitis, with a relatively nonprogressive
form of the disorder.
Results: In our patients, clinical features were dominated by partial seizures
without marked focal motor deficit and in two with choreo-dystonic movements. The
diagnosis of RE was supported by histologic examination and anatomic and functional
MRI.
Conclusions: These cases extend the phenotypic presentations of Rasmussen
encephalitis and confirm Theodore Rasmussen’s suggestion that there may be
mild and nonprogressive forms of the disease.
NEUROLOGY 2008; 70:374-377
Paraneoplastic syndromes of the CNS
Josep Dalmau, Myrna R Rosenfeld, Division of Neuro-oncology, University of Philadelphia
Major advances in the management of paraneoplastic neurologic disorders (PND) include
the detection of new antineuronal antibodies, the improved characteristics of known
syndromes, the discovery of new syndromes, and the use of CT and PET to reveal the
associated tumours at an early stage. In addition, the definition of useful clinical
criteria has facilitated the early recognition and treatment of these disorders.
In this article, we review some classic concepts about PND and recent clinical and
immunological developments, focusing on paraneoplastic cerebellar degeneration,
opsoclonus-myoclonus, and encephalitides affecting the limbic system.
LANCET NEUROL 2008:7:327-40
Multiple Sclerosis, Acute Disseminated Encephalomyelitis, and Related Conditions
Robert S. Rust
Multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM) are conditions
whose closely related pathology suggests shared pathophysiological elements, but
whose clinical courses are usually, but not always quite dissimilar. The former
is largely a disease of adulthood, the latter of childhood. Optic neuritis, demyelinative
transverse myelitis, and Devic's syndrome are neurological syndromes that may occur
as manifestations of either MS or ADEM. Patients with Miller-Fisher syndrome and
encephalomyelradiculoneuropathy usually have features suggesting ADEM in combination
with acute demyelinative polyneuropathy. These various conditions and other forms
of ADEM share an indistinct border with encephalitides, granulomatous, and vasculitic
conditions. MS, ADEM, and the pertinent syndromic subtypes, their differential diagnosis,
treatment, and prognosis are considered in this review. Acute cerebellar ataxia
is a syndrome that is likely to be pathophysiologically distinct from ADEM, although
its occurrence as a postinfectious illness suggests a distant kinship. It is also
reviewed.
Seminars in Pediatric Neurology, Vol 7, No 2 (June), 2000: pp 66-90
Potassium Channel Antibodies in Two Patients with Reversible Limbic Encephalitis
Camilla Buckley, MD, Joel Oger, MD, Linda Clover,BSc, Erdem Tűzűn,
MD Katherine Carpenter, Dip Psych, Matthew Jackson, MD, Angela Vincent, FRCPath
Limbic encephalitis (LE) is often associated with lung, thymic, or testicular tumours
and antibodies to Hu, CV2 or Ma2 (Ta) antigens. In these cases, it generally has
a poor prognosis. Here we describe two patients with symptoms of LE, negative for
typical paraneoplastic antibodies, in whom antibodies to voltage-gated potassium
channels (VGKC) were detected in the years following presentation. Plasma exchange
was effective in reducing VGKC antibody levels, with substantial improvement in
mental symptoms in patient 1. In patient 2, the VGKC antibodies fell spontaneously
over two years, with almost complete recovery of mental function. Although neither
patient had obvious neuromyotonia at presentation, both showed excessive secretions.
We suggest that patients with limbic symptoms and excessive secretions should be
tested for VGKC antibodies, and, if they are present, prompt and effective immunosuppressive
treatment should be considered.
Ann Neurol 2001; 50:73-78
BK virus DNA in CSF of immunocompetent and immunocompromised patients
A Behzad-Behbahani1, P E Klapper2, P J Vallely3 and G M Cleator3
Aim: To investigate the possible aetiological role of BK and JC viruses in
immunocompetent and immunocompromised children with suspected encephalitis and meningoencephalitis.
Methods: The polymerase chain reaction and microplate hybridisation method
was employed for the detection of polyomavirus DNA in 266 CSF specimens collected
from immunocompetent and immunocompromised patients.
Results: BK virus DNA was detected in three (2.1%) CSF samples taken from
patients aged 2–5 years; two were patients with acute lymphocytic leukaemia
without overt neurological symptoms, the other was a patient with suspected encephalitis.
BK virus DNA was also detected in two (1.6%) CSF samples taken from older children
in the age range 10–16 years; both children had suspected encephalitis. JC
virus DNA was not found in any CSF sample from either age group.
Conclusions: Detection of BK virus in the CSF of immunocompromised and immunocompetent
patients with suspected neurological disease suggests that this virus may have had
a pathogenic role in the aetiology of this condition.
http://adc.bmj.com/
Last modified: September 2010