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AUTOIMMUNE ENCEPHALITIS: A MISSED DIAGNOSTIC AND THERAPEUTIC OPPORTUNITY

ABSTRACT

Encephalitis is a common clinical problem affecting 5 cases per 100 000 population annually. After exclusion of the usual infective causes, a number of cases remain unexplained. It has been observed that many such cases have an autoimmune basis resulting in disruption of synaptic and ion channel function. This diagnosis should be suspected based on subacute onset, short term memory loss, altered mental status or psychiatric symptoms in combination with new focal neurological deficits, new onset seizures, CSF pleocytosis or MRI features suggestive of encephalitis. As this is a treatable condition, with a good prognosis if recognised early, it is important not to miss the diagnosis.

Key Words: Autoimmune encephalitis


BACKGROUND AND HISTORY

The term encephalitis refers to a rapidly progressive encephalopathy (usually in less than 6 weeks) as a result of brain inflammation and has an estimated annual incidence of 5 cases per 100 000 population in a UK cohort.[22, 72] This clinical scenario is quite rightly, in the first instance, considered to have an infectious cause as any delay in the diagnosis and treatment is associated with a high morbidity and mortality. For example, a more than two day delay in treatment initiation of Herpes simplex encephalitis results in a three-fold worse outcome at 6 months.[62] In approximately 50% of cases, the aetiology remains undetermined but with increased awareness many cases previously labelled as idiopathic encephalitis are now being identified to have an autoimmune origin.[47, 77] In view of the initial presentation, many of these patients are mistakenly thought to have a psychiatric disorder resulting in a delay in treatment.

The first description of paraneoplastic limbic encephalitis was in 1968 in association with lung, breast and thyroid malignancies.[9] These patients had paraneoplastic anti-Hu or anti-Ma2 antibodies: intracellular antibodies that result in irreversible, cytotoxic T cell responses with a poor prognosis and poor response to therapy. In 2005 Ances et al described 8 patients with limbic encephalitis who, at that time, had unidentified antibodies to neuronal surface proteins.[3] There has since been continued discovery of 1-2 such antibodies per year.[51] These antibodies reversibly disrupt synaptic functions and ion channels and are thus responsive to immunotherapy.[3] Unlike the intracellular neuronal antibodies, these neuronal cell surface antibodies have a more variable association with underlying malignancy (Table 1). In addition, autoimmune encephalitis affects patients of all age groups and detection has diagnostic, prognostic and therapeutic importance.

In this review, we discuss the clinical presentation of two of the most common autoimmune encephalopathies supported with case studies. We suggest a practical diagnostic approach to these patients.


Table 1: Autoimmune Encephalitis Syndromes

Clinical Presentation
Neuronal intracellular antibodies
Hu [1, 23] Limbic encephalitis* 28-82 (63) 75% male >95% SCLC
Ma2 [12] Limbic encephalitis* 22-70 (34) 68% male >95% Testicular
GAD [55] Limbic encephalitis*, stiff person syndrome >50 90% male 25% Thymoma; SCLC
Neuronal cell surface antibodies
NMDAR [13, 52] Psychiatric, seizures, movement disorder, autonomic dysfunction, coma 0.6-85 (21) 80% female Varies with age and gender Ovarian teratoma (females 12-45y)
LGI1 [34, 43] Limbic encephalitis*, Faciobrachial dystonic seizures, Hyponatraemia 30-80 (60) 65% male 5-10% Thymoma, thyroid, lung, renal cell
CASPR2 [34, 45, 71] Limbic encephalitis*, Morvan’s syndrome†, Neuromyotonia 46-77(60) 90% male 20-50% Thymoma
GABA A [60] Encephalitis, refractory seizures 3-63 (22) 83% male <5% Thymoma
GABA B [46] Limbic encephalitis*, seizures 16-77 (62) 50% male 50% SCLC
AMPAR [42] Limbic encephalitis* 38-87 (60) 90% female 70% SCLC, breast, thymoma
Glycine [8] PERM, stiff person syndrome, limbic encephalitis* 1-75 (49) 53% male 10% Thymoma, lymphoma, breast
mGLuR5 [48] Encephalitis, myoclonus 15-46 50% male 70% Hodgkin’s Lymphoma
DPPX [5] Encephalitis, PERM, hyperekplexia 15-76 65% male <10% Lymphoma
DR2 [11] Basal ganglia encephalitis, movement disorders 1-15 (5) 50% male Nil No association
IgLON5 [19] Sleep disorder, cognitive dysfunction, bulbar symptoms 46-83 (64) 54% female Nil No association

*Limbic encephalitis: subacute confusion, memory disturbance, neuropsychiatric features and seizures.

†Morvan’s syndrome: cognitive symptoms or seizures, peripheral nerve hyperexcitability and insomnia

Abbreviations:

AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor;

CASPR2, contactin-associated protein-like 2;

DR2, dopamine receptor 2;

DPPX, dipeptidyl-peptidase-like protein-6;

GABAR, gamma-amino-butyric acid receptor;

GAD,glutamic acid decarboxylase;

IgLON5, immunoglobulin-like family member 5;

LGI1, leucine-rich, glioma-inactivated 1;

mGluR5, metabotropic glutamate receptor 5;

NMDAR, N-methyl-D-aspartic acid receptor;

PERM, progressive encephalomyelitis with rigidity and myoclonus.


METHODS

Relevant articles were identified through PubMed searches of articles published in English up to 1 May 2017. Search terms included (alone or in combination) encephalitis, encephalopathy, limbic or autoimmune, which yielded 358 results. Additional articles were identified in references. Priority was given to large case series.
Written consent was obtained from patients described in the case reports.

ANTI-NMDA RECEPTOR ENCEPHALITIS

This disorder is associated with IgG antibodies against the GluN1 subunit of N-methyl D-aspartate (NMDA) receptors.[20] In vitro studies have shown that antibodies bind to NMDA receptors resulting in cross-linking and internalization. The degree of damage correlates with antibody titres and reverses with antibody removal.[31]

NMDA encephalitis has been found to be a common cause of encephalitis and the most common form of autoimmune encephalitis.[13] In an English series, 4% of patients with encephalitis were diagnosed with NMDA encephalitis.[21] The California encephalitis cohort identified NMDA encephalitis as being the most common cause of encephalitis, 4 times more common than viral causes, although this cohort was likely influenced by referral bias.[18] An intriguing finding is that in some patients herpes simplex encephalitis may also trigger other autoimmune reactions such as NMDA encephalitis.[15, 27]

The earliest reports of NMDA encephalitis were in 2005 and 2007 when Vitaliani and Dalmau described young women with ovarian teratomas presenting with psychiatric abnormalities, movement disorders and central hypoventilation.[14, 76] These descriptions resulted in rapid identification of increasing numbers of cases, with more than 600 cases being described in the literature by 2013.[68]

The clinical presentation and association with an underlying tumour varies with age and gender. The median age of presentation is 21 years but has ranged from 8 months to 81 years. Eighty one percent of the patients are female. Associated tumours are present in 38% of patients, predominantly in females between the ages of 12 and 45. Males are more likely to present below the age of 12 or over 45. Ninety seven percent of the associated tumours occur in females, 94% of which are ovarian teratomas. The remainder of tumours are extraovarian teratomas, lung, breast, testicular, ovarian, thymic and pancreatic in origin.[68]

These patients typically present in a step wise manner, although steps may occur in any order, all steps do not have to be present and seizures can occur at any stage of disease.

In 70% of patients a prodrome may precede the onset of other symptoms by up to 2 weeks. Prodromal symptoms include headache, fever, nausea, diarrhoea or features of an upper respiratory tract infection. Psychiatric symptoms occur next and range from anxiety and insomnia to mania, paranoia, hallucinations and grandiose delusions.[32, 63] In some patients psychiatric symptoms may predominate, resulting in psychiatric admission.[61] Atypical features for schizophrenia, such as pronounced catatonia or associated movement disorders and seizures, should therefore prompt psychiatrists to exclude an underlying autoimmune encephalitis.[70] Short term memory loss is common. Subsequent symptoms include movement disorders, autonomic dysfunction and central hypoventilation. The range of movement disorders is vast including chorea, dystonia, oro-lingual dyskinesias and opisthotonic posturing. The presence of autonomic dysfunction and central hypoventilation often necessitates ventilation and support in an intensive care setting.[32, 63]

Monosymptomatic presentations are very rare in all age groups but males more commonly present with partial seizures.[57, 73] Even though the presenting symptoms may vary by age, within 4 weeks the majority of patients have developed a similar cluster of symptomatology.[68]

Patients with long-term psychiatric diagnoses have on occasion been found to have NMDA receptor antibodies. The majority of these patients do not have other symptoms described in the syndrome. It is important to note in these patients have IgA or IgM and not IgG antibodies, or antibodies against the GluN2 subunit, and not GluN1 subunit that has been associated with NMDA encephalitis. [6, 28, 41] Four percent of patients have been described to have an overlapping, concurrent or sequential demyelinating syndrome, sometimes with associated Aquaporin 4 antibodies.[67]

With treatment 53% of patients improve within 4 weeks and 80% at 24 months. Symptoms often resolve in the reverse order in which they presented. First line treatment consists of tumour removal (if present), steroids, intravenous immunoglobulins and plasmapharesis. Up to 40% of patients do not respond to first line therapy. Second line therapy consists of rituximab or cyclophosphamide (individually or in combination). Approximately 80% of patients who fail first line therapy have a good outcome at 24 months after second line therapy. [68] It is important to keep in mind though that even after improvement of the acute episode there may be persistent deficits in memory, executive function and behavioural disturbances.

The condition is associated with a 7% mortality rate and relapses occur in 12-20%. Relapses may be separated from the initial event by months to years, consist of only part of the initial syndrome and are usually less severe than the initial episode.[17, 68] Relapses are also more likely to occur if the presenting episode was not treated or undertreated.[35] Although relapses are less common in those who were treated for an underlying tumour, in the case of a relapse patients should be re-assessed for presence of underlying contralateral or recurrent teratoma.[32]

CASE REPORT: NMDA ENCEPHALITIS (IN A BOX)

A previously well 19 year old woman was referred to the neurology unit for investigation of a change in her mental state. Five days prior to presentation she reported hearing unfamiliar voices while studying and feeling suspicious of others. Two days later she stopped responding to those around her and subsequently had two generalised tonic clonic seizures. There was no viral prodrome. On examination she was unresponsive to any stimuli and had prominent oromandibular dyskinesias, dystonia and opisthotonic posturing. She required intubation, ventilation and ICU admission. While in ICU she had episodes of supraventricular tachycardia. The patient was commenced on IVI acyclovir and investigated for an encephalitis. The FBC and metabolic panels were normal, HIV ELISA negative and RPR non-reactive. A lumbar puncture showed 8 lymphocytes, 0 polymorphonuclear cells, protein 0.16 g/l, glucose 4.4 mmol/l (plasma 7 mmol/l). The CSF FTA and cryptococcal latex agglutination test were negative, as were the PCR assays for HSV, VZV and CMV. NMDA receptor antibodies were negative in the serum but positive in CSF. The EEG was in keeping with an encephalopathic state with an extreme delta brush pattern. MRI brain was normal. Pelvic ultrasound did not show an underlying ovarian teratoma. The patient did not respond to first line therapy with IV methylprednisone, intravenous immunoglobulins or plasma exchange. She subsequently improved after 5 doses of IV cyclophosphamide. After a three-month admission to ICU she was stepped down to a general ward. She was discharged home two months later with continued outpatient rehabilitation. The patient was continued on oral prednisone and azathioprine and has continued to improve. One year later she is considering resuming her postgraduate studies.

VOLTAGE-GATED POTASSIUM CHANNEL ANTIBODIES

Voltage-gated potassium channels (VGKC) form part a multiprotein neuronal complex. Prior to 2010 antibodies to the Kv1.1 and Kv1.2 subunits of the Shaker family of VGKC were recognised in association with limbic encephalitis, faciobrachial dystonic seizures, Morvan syndrome and neuromyotonia.[33, 66, 74] Subsequently it has been identified that contactin-associated protein-2 (Caspr2) and leucine-rich, glioma inactivated 1 protein (LGI1) are the true target antigens, each with unique clinical presentations.[34, 43, 71] References to VGKC encephalitis prior to 2010 was most likely referring to an encephalitis secondary to LGI1 antibodies. Antibodies to other extracellular domains of the VGKC are not pathogenic and do not require treatment with immunotherapy.[49]

LGI1 ANTIBODIES

LGI1 is a protein that interacts with the pre-synaptic ADAM23 and post-synaptic ADAM22 and AMPA receptors, forming a trans-synaptic complex. It is postulated that the antibodies result in reduced AMPA inhibitory behaviour, therefore resulting in neuronal hyperexcitability.[58]

LGI1 antibodies result in the second most common form of autoimmune encephalitis, after NMDA.[52] The disorder has a male predominance, with a 2:1 male:female ratio and a median age at presentation of 63 years.[34, 36] The typical presentation is that of faciobrachial dystonic seizures affecting the arm and ipsilateral face, which may precede the onset of limbic encephalitis by up to 26 days.[36] These seizures last about 3 seconds each and may occur a median of 50 times per day. Identification of the disorder at this stage is important as early treatment may prevent the rest of syndrome from developing and improves the prognosis.[38] Limbic encephalitis then develops, which consists of subacute onset confusion, short-term memory disturbance and personality changes.[34] Patients may then go on to develop generalised tonic clonic seizures, focal seizures with impaired awareness of temporal lobe origin or focal seizures with associated piloerection.[34, 74, 79] Presentation in non-convulsive status is not uncommon. As these seizures do not respond to anticonvulsants but to immunosuppressive therapy the identification of the disorder is very important.[36] A unique feature of LGI1 encephalitis is hyponatraemia, which occurs in 60-88% of cases. This is thought to be due to LGI1 antibodies binding to antidiuretic hormone-secreting neurones.[37] In the majority of patients, there is no tumour association. Prognostically, 71% of patients are seizure free with monthly IV MTP but only 33% had normalization of memory.[54] Rapid identification and treatment of this disorder is important as a delay in institution of immunotherapy has been associated hippocampal atrophy and poorer long-term memory outcome.[16] Therefore, despite patients with LGI1 encephalitis having a more rapid response to treatment than those with NMDA encephalitis it is likely that they have a poorer long-term recovery.[51] Reported mortality is 6% and relapses occur in 15%.[34, 43]

CASPR2 ANTIBODIES

Disease associated with Caspr2 antibodies is more diverse, consisting of central and peripheral nervous system involvement. Limbic encephalitis (42%) and Morvan syndrome (29%) are the most frequent clinical syndromes and develop over an average of 4 months.[71] Morvan syndrome refers to a combination of cognitive symptoms or seizures, peripheral nerve hyperexcitability and insomnia.
This condition occurs predominantly in males with a median age of 66, 20% of which have associated thymomas.[37, 71, 75] Although these patients show a good response to immunotherapy relapses occur in 25%.[45, 71]

CASE REPORT: LGI1 ENCEPHALITIS (IN A BOX)

A 65 year old man with a background history of diabetes and hypertension presented in April 2014 with a first episode generalised tonic clonic seizure lasting 10 minutes. He had no further neurological complaints and a normal neurological examination. He also had features of a right middle lobe pneumonia and cholangitis. The serum Na was 117 mmol/L with a urinary Na of 75 mEq/L, urine osmolality of 536 mOsm/kg and serum osmolality of 269 mOsm/kg. This was interpreted as syndrome of inappropriate ADH on the basis of underlying septicaemia, complicated by a seizure. A CT brain was normal. The underlying septicaemia was treated and he was commenced on fludrocortisone tablets and water restriction.
The patient was readmitted in June with further seizures and persistent hyponatraemia. His EEG was in keeping with a mildly encephalopathic state. A lumbar puncture was performed and showed 0 polymorphs, 24 lymphocytes, protein 0.54 mg/dL, glucose 3.7 mmol/L (serum 6) and was negative for oligoclonal bands. The CSF FTA, HSV, VZV, m