Autoimmune limbic encephalitis—typical presentation is with acute or subacute onset of short term memory loss, seizures and disorientation. MRI characteristically shows striking abnormalities in the hippocampus. Antibodies against cell-surface proteins that are components of voltage-gated potassium channel (VGKC) complexes are found in a high proportion and are probably pathogenic. Aside from supportive care, treatment is with immunosuppression, often comprising corticosteroids with intravenous immunoglobulin and/or plasma exchange.
Morvan’s syndrome—a very rare condition presenting with varying degrees of neuromyotonia, memory loss, confusion, sleep disturbance, and autonomic features, also with antibodies to VGKC-complex proteins. About 50% have VGKC antibodies.
Autoimmune limbic encephalitis (LE) with VGKC-complex antibodies
Since its first recognition in 2001, 100s of patients have been identified with LE associated with antibodies that immunoprecipitate VGKC-complex proteins. Preliminary epidemiology suggests that it is more common in men (2:1) and that the median age at onset is 65 years. The phenotype has been recognized mainly in patients over the age of 18 years at onset.
The classic presentation is with subacute onset of short-term memory loss, seizures, disorientation, with psychological disturbance or hallucinations. Additional features that may occur are sleep disturbance, autonomic dysfunction, and neuromyotonia but these would be more typical of Morvan’s syndrome (see below). The most striking feature on examination is the profound disorientation and memory loss, leading to poor performance on bedside cognitive tests such as the Mini-Mental State Examination. Neuromyotonia (see Chapter 24.21) may be evident, but often the examination is otherwise unremarkable. Some patients develop only one aspect of the syndrome (e.g. isolated memory loss or isolated temporal or frontal seizures), but are otherwise similar to those with the full syndrome. Some patients report an influenza-like illness 1 to 2 weeks earlier. Recently, an increasing number have been patients with immunotherapy-responsive brief frequent dystonic seizures that precede the limbic disturbance by days to weeks.
Hyponatraemia is present in 80% of patients, usually accompanied by a low plasma and urine osmolarity. Other routine blood tests are normal. The cerebrospinal fluid is often normal but may show a mild pleocytosis. Voltage-gated potassium channel (VGKC)-complex antibody titres are characteristically very high in these patients (more than 400 pmol/litre and often more than 1000 pmol/litre (normal range less than 100 pmol/litre)), and higher than the titres commonly found in patients with neuromyotonia (usually less than 400 pmol/litre) (Fig. 24.22.1b). MRI shows striking abnormalities in 70% of patients and it is often these that lead the clinician to suspect the diagnosis and request the confirmatory serological test (Fig. 24.22.1a). The most classic change is high signal restricted to the hippocampus (either unilaterally or bilaterally), best seen on T2-weighted or FLAIR (fluid-attenuated inversion recovery) sequences, with associated swelling of the affected area. A few patients have more widespread areas of increased signal in the medial temporal lobes and amygdala. LE associated with VGKC antibodies can occasionally (<10%) be a paraneoplastic disorder and so all patients should undergo appropriate imaging to detect any underlying malignancy (e.g. thymoma or small-cell lung cancer).
VGKC-complexes are extracted from brain tissue and include the Kv1 shaker-type VGKCs and other interacting proteins, particularly leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2). The antibodies can be identified by immunoprecipitation of VGKC-complexes, or by binding to the individual proteins. In LE, they are most often directed to LGI1.
Initially patients often require fluid restriction to manage the hyponatraemia, antiepileptic drugs for their seizures, antipsychotic drugs to control paranoid ideation, and corticosteroids with plasma exchange or intravenous immunoglobulin (IVIG) for acute immunosuppression. The choice of antiepileptics is complicated by the hyponatraemia, which can be profound. Often the seizures do not respond well to antiepileptics alone and do not start to reduce in frequency until immunosuppression has been established.
There have been no randomized controlled trials to determine the most effective immunosuppressive regimens in these patients and so currently the protocols are similar to those used to treat patients with autoimmune disorders of the neuromuscular junction (see Chapter 24.23). Corticosteroids appear to be a particularly important component because longer-term follow-up suggests that those treated with IVIG alone respond less well than those treated with IVIG and steroids. Although early treatment is recommended, as it appears to be associated with improved prognosis, even late introduction of steroids and other immunosuppression can be beneficial.
Acutely the differential diagnosis lies mainly with infectious causes of LE, the most common being herpes simplex encephalitis (HSE), and most patients will have a CSF polymerase chain reaction for HSE performed on admission, particularly if they have a high fever and severe headache. Korsakoff’s pyschosis can present similarly and so an accurate alcohol history and suggestive blood tests such as liver function tests and mean cell volume (MCV) should be performed.
The other main differential lies with paraneoplastic LE, so all patients need imaging to detect associated tumours and, in the right context, it may be appropriate to look for the particular antibodies seen with these disorders (see Chapter 24.21). Other forms of potentially immunotherapy-responsive LE are now being recognized some of which are associated with antibodies to other neuronal surface antigens (e.g. N-methyl-D-aspartate receptor, see Chapter 24.21) can be non-paraneoplastic. Morvan’s syndrome, although very rare, can present similarly to LE and is distinguished by additional peripheral and autonomic features (see below). In addition (as with the autoimmune disorders of the neuromuscular junction), there are patients with a similar clinical phenotype who respond to immunomodulatory therapies, but in whom no antibody is detectable by current methods, although new diagnostic tests will undoubtedly emerge.
VGKC-complex LE is probably an immune-mediated disorder given the time course of patients’ clinical, serological, and radiological responses to immunosuppression. VGKC is a transmembrane protein that is densely expressed in the hippocampus and elsewhere in the brain, where it is complexed with LGI1, CASPR2, and other proteins. Genetic mutations in VGKC can cause seizures both in mice and in humans and, as the channel is involved in stabilizing the membrane potential, its dysfunction will result in neuronal hyperexcitability. It is likely that the antibodies have a direct role in the pathogenesis, but they may just be a very useful clinical biomarker for this treatable immune-mediated disorder.
This is a very rare condition in which patients present with varying degrees of neuromyotonia, central nervous system symptoms such as memory loss, confusion, and sleep disturbance, and additional autonomic features such as constipation and cardiac arrhythmias. Few cases have been described, but the majority have VGKC-complex antibodies, usually at levels intermediate between neuromyotonia and VGKC LE; these are directed more often to CASPR2 than to LGI1. Thymoma is more common than in VGKC LE or neuromyotonia (c.50%), and can be aggressive, but most patients do well with thymectomy, if appropriate, and immunosuppression, and some appear to have a self-limiting disease.
Buckley C et al. (2001). Potassium channel antibodies in two patients with reversible limbic encephalitis. Ann Neurol, 50, 73–8.Find this resource:
Graus F, et al. (2008). Neuronal surface antigen antibodies in limbic encephalitis: clinical-immunologic associations. Neurology, 71, 930–6.Find this resource:
Irani SR, et al. (2010). 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. Brain, 133, 2734–48.Find this resource:
Irani SR, et al. (2011). Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol, 69, 892–900.Find this resource:
Irani SR, et al. (2012). Morvan syndrome: Clinical and serological observations in 29 cases. Ann Neurol, 72, 241–55.Find this resource:
Vincent A et al. (2004). Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain, 127, 701–12.Find this resource:
Vincent A et al. (2011). Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol, 10, 759–72.Find this resource: