Voltage-gated potassium channel antibody (VGKC-Ab)-associated limbic encephalitis (LE) is a recently described syndrome that broadens the spectrum of immunotherapy-responsive central nervous system disorders. Limbic encephalitis is typically characterised by a sub-acute onset of disorientation, amnesia and seizures, but the clinical spectrum is not yet fully defined and the syndrome could be under-diagnosed. We here describe the clinical profile of four patients with VGKC-Ab-associated LE who had intermittent, episodic hypothermia. One of the patients also described a prodrome of severe neuropathic pain preceding the development of limbic symptoms. Both of these novel symptoms responded well to immunosuppressive therapy, with concurrent amelioration of amnesia/seizures.
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Limbic encephalitis (LE) is a clinical diagnosis based on the sub-acute development of disorientation, amnesia and seizures. Traditionally, LE is considered to be a paraneoplastic condition, associated with small-cell lung cancer (SCLC), thymoma and other tumours.1 More recently, voltage-gated potassium channel antibodies (VGKC-Abs), which were originally described in peripheral nerve hyper-excitability syndromes, have been identified in cases of LE,2–4 but only a few of these patients have thymoma or SCLC and most do well after immunosuppressive treatments.2–4 VGKC-Abs are also found in patients with Morvan’s syndrome, which is characterised by neuromyotonia, autonomic and CNS dysfunction, and is often associated with pain in muscle, skin or joints.5 6 Overall, the range of clinical presentations of immunotherapy-responsive VGKC-Ab-associated syndromes is not well defined, and there may be under-recognition. Here, we describe four patients (summarised in table 1) with LE associated with hypothermia, one of whom presented initially with neuropathic pain.
A 46-year-old lady was admitted to her local hospital with a 10-week history of intractable, sharp and burning, multi-dermatomal lower back pain. Investigations, including MRI thoracolumbar spine with contrast and CT abdomen/pelvis, were normal, and no definite diagnosis was made. A few weeks later, the patient was found in a confused state, with episodic visual hallucinations. She had lost appetite and weight over the preceding 4 months. On transfer to the neurology unit, she had a fluctuating level of cognition, hypothermia (ranging from 34 to 35.5°C; transiently as low as 33°C) and excessive sweating. There were no other objective neurological signs. VGKC-Ab was strongly positive (869 pM; controls <100 pM) (fig 1).
Contrast-enhanced brain MRI, and two EMG/nerve conduction studies looking specifically for neuromyotonia, were normal. CT thorax showed a thymic nodule and thymectomy revealed a cortical thymoma (type B2). Following a course of intravenous immunoglobulin (IVIg) and azathioprine initiation, there was rapid resolution of hypothermia, autonomic and cognitive dysfunction. The back pain, which was present throughout her stay and previously refractory to gabapentin, amitryptilline and carbamazepine, also resolved. VGKC-Ab assay was unfortunately not performed during this remission.
Four months after azathioprine withdrawal (secondary to an aplastic crisis), the patient developed a relapse of hypothermia, hyperhidrosis and weight loss, which was again preceded by sharp and burning pain for 2 months—this time affecting her legs, chest and abdomen. VGKC-Ab was positive (295 pM). A course of IVIg was given, followed by oral prednisolone, with resolution of hypothermia and neuropathic pain. She is currently asymptomatic on maintenance ciclosporin, 4 years after the initial presentation, with the VGKC-Ab now negative.
This 72-year-old male presented with new-onset seizures, episodic confusion and memory deficits. His core body temperature ranged from 34.5°C to 35.9°C for almost 6 weeks with no other autonomic features. The VGKC-Ab on initial diagnosis was 2135 pM. He was treated with plasma exchange and IVIg, with significant improvement of all symptoms, including the hypothermia. The VGKC-Ab titre gradually reduced to the normal level and has remained so for 2 years (fig 1). There was no evidence of a thymoma or other tumours.
This lady presented with gradual, progressive memory loss beginning at the age of 57 years. She had difficulty performing several activities of daily living and was initially given a presumptive diagnosis of Alzheimer’s disease. A few years later, she developed infrequent episodes of complex partial seizures. The MRI, performed 6 years after the disease onset, showed bilateral hippocampal atrophy with a high signal in the right medial temporal lobe. In view of the increasing frequency (2–3 per week) of temporal lobe seizures, she was referred to the regional neurological service. On examination, the patient was disorientated in time and place, with defects in verbal recall and visuo-spatial memory. She also had high-level semantic memory deficits. Her VGKC-Ab was raised at 591 pM. At this time, her temperature was noted to fall transiently to 34.8°C, without accompanying symptoms. She was treated with IVIg, followed by carbamazepine, with complete cessation of seizures within 2 weeks. The repeat VGKC-Ab titre 2 months after IVIg was 365 pM. There was some improvement in her memory, with the patient now performing some daily household tasks that she was unable to perform previously.
This patient has been described previously as a case of “idiopathic” LE with transient hyponatraemia and hypothermia (lowest recorded temperature 33°C),9 and MRI changes consistent with inflammation in the hypothalamus and medial temporal lobes. This profile was thought to be consistent with VGKC-Ab associated LE7 and retrospective analysis of serum showed high titres of VGKC-Ab, 2354 pM, which fell to 901 pM after the initial course of immunosuppression.8 The patient is currently on a low dose of steroids (prednisolone 10 mg daily) and has improved considerably with only minor deficits in memory and orientation. His latest VGKC-Ab titre was negative.
VGKC-Ab-associated LE usually presents with cognitive impairment, confusion and disorientation, and the majority of patients develop seizures at some stage during their acute illness.3 Patients with this reversible amnesic syndrome tend to be predominantly middle-aged,2–4 with a male:female ratio of 2:1 (AV, unpublished observation). Many patients have hyponatraemia, medial temporal lobe signal changes in the MRI, and diffuse or focal activity in their EEG.3 4 The VGKC-Ab titres correlate broadly with clinical response.3 The four cases presented here are interesting because the presence of hypothermia, and an immunoresponsive neuropathic pain syndrome in one, widen the spectrum of clinical presentations associated with VGKC-Ab-associated LE.
Hypothermia (body temperature less than 35°C) is an established feature of autonomic dysfunction, and in the patients described, is likely to be secondary to alteration of the thermoregulatory mechanisms in the hypothalamus. Hypothermia has been reported in some patients with Ma-2 and anti-NMDA-receptor antibody-associated paraneoplastic LE who often have more widespread CNS involvement,10 11 but has not been previously described in cases of VGKC-Ab-LE, which is generally thought to be restricted to the hippocampus and mesial temporal lobe. However, reports of hyponatraemia, somnolence, hypersalivation and marked appetite alterations in some VGKC-Ab-positive patients with either LE or Morvan’s syndrome3 4 6 suggest that neuroendocrine hypothalamic dysfunction can be a manifestation of VGKC-Ab-associated disease. It should be noted that three of the four patients (patients 1, 2 and 4) had hypothermia lasting for at least 24 hours. For patient 3, the temperature was 35±0.5°C for almost 48 hours.
Intractable neuropathic pain has never been described as a symptom of VGKC-Ab-associated LE, but the improvement with immunosuppressive therapy suggests that this was likely to be part of her VGKC-Ab-associated paraneoplastic syndrome (fig 1). In Morvan’s syndrome, which is also associated with VGKC-Abs, myalgia, muscle cramps, pruritus and joint pain have been described.5 6 Interestingly, potassium channel agonists can have an anti-nociceptive effect12 and the VGKC-Abs, by downregulating the potassium channels, may have produced a nociceptive response.
The lack of an effective blood–brain barrier in the circumventricular organs may explain how antibodies produce hypothalamic manifestations in a subset of patients. Although it is not clear why the hippocampus is predominantly affected in most cases to date, factors known to disrupt an intact blood–brain barrier, including neurodegeneration (eg Alzheimer’s disease, a possibility in Patient 3) and infection3 may play a “triggering” role.
Most neurological disorders with a probable antibody-mediated aetiology show a sub-acute onset and VGKC-Ab-mediated LE is no exception. The first reported case2 had a monophasic pattern to her illness and improved without therapy. This monophasic pattern is the typical disease course seen in VGKC-Ab-mediated LE. Patient 3 demonstrates a much more protracted and chronic course and highlights the potential spectrum of presentations. Indeed, it is debatable whether patient 3 had a history of chronic autoimmune encephalopathy or whether the VGKC-Ab-mediated LE was superimposed on a pre-existing cortical illness.
VGKC-Ab should be measured in patients with otherwise unexplained encephalopathic symptoms, with or without hypothalamic dysfunction. Hypothermia or neuropathic pain could be under-recognised manifestations of paraneoplastic LE or VGKC-Ab-associated LE/Morvan’s syndrome. Thymoma or other tumours (SCLC) should always be excluded, and treatment of any underlying neoplasm,1 combined with prolonged immunosuppression,2–4 may lead to complete reversal of the neurological symptoms.
The authors would like to thank Ms Sarah Flanagan of University Hospitals of Coventry and Warwickshire, for her valuable secretarial assistance.
Funding: This work was supported in part by a grant from the DANA Foundation. SI is supported by the National Institute of Health Research, Department of Health, UK.
Competing interests: The University Department of Clinical Neurology in Oxford receives royalties and payments for VGKC and other antibody assays.