Autoimmune encephalitis

Autoimmune Encephalitis
Classification and external resources
Specialty
ICD-10	G04.81
ICD-9-CM	323.81
Patient UK	Autoimmune encephalitis

Autoimmune encephalitis (or autoimmune encephalopathy) is a diverse group of neuro-psychiatric disorders recognized recently, presenting acutely or subacutely with alteration of consciousness, cognitive decline, seizure, abnormal movements. Associated with systemic autoimmune disorders, CNS autoimmune disorders and paraneoplastic syndromes. Pathogenesis is likely to be mediated by antibodies (Abs) to CNS proteins. The Abs are directed against membrane receptors and ion channel-associated proteins that are expressed on the surface of neurons in the CNS, such as N-methyl D-aspartate receptors and leucine-rich, glioma inactivated protein and contactin-associated protein like, that are associated with voltage-gated potassium channels. The diseases are not invariably cancer-related and are therefore different from the classical paraneoplastic neurological diseases that are associated with, but not caused by, Abs to intracellular proteins. Diagnosis of autoimmune encephalopathy is based on the clinical course, serologic evidence of autoimmunity, severe but nonspecific slowing on electroencephalography, and evidence of intrathecal inflammation in the cerebrospinal fluid and neuroimaging by MRI. Treatment include first-line steroids, intravenous immunoglobulins(IVIG), and plasma exchange, and second-line Rituximab and Cyclophosphamide, followed in many cases by steroid-sparing agents in the long-term.

Neurological Syndromes Associated with Autoimmune Antibody (NSAAA)

Sydenham's chorea (SC)

Main article: Sydenham's chorea

Sydenham's chorea epidemic was first documented in 1418 and later in 1686 Thomas Sydenham described the condition. The association of chorea with rheumatism was first recognized in 1802 and several cases has been reported by French and English workers during nineteenth century. It was Richard Bright who in 1831 who first made the association between chorea and rheumatic fever. The evidence suggesting that it may be mediated by streptococcal antibodies that cross-react with the brain was published in 1993.

Encephalitis Lethargica (EL)

Main article: Encephalitis Lethargica (EL)

In 1916, von Economo described encephalitis lethargica (EL), a CNS disorder presenting with pharyngitis followed by sleep disorder, basal ganglia signs (particularly parkinsonism) and neuropsychiatric sequelae. Since the 1916–1927 epidemic, only sporadic cases have been described. Pathological studies revealed an encephalitis of the midbrain and basal ganglia, with lymphocyte (predominantly plasma cell) infiltration. The EL epidemic occurred during the same time period as the 1918 influenza pandemic, and the two outbreaks have been linked in the medical literature. However, von Economo and other contemporary scientists thought that the 1918 influenza virus was not the cause of EL. Recent examination of archived EL brain material has failed to demonstrate influenza RNA, adding to the evidence that EL was not an invasive influenza encephalitis. By contrast, the findings of intrathecal oligoclonal bands (OCB) and beneficial effects of steroid treatments have provoked the hypothesis that EL may be immune‐mediated.

Hashimoto's encephalopathy

Main article: Hashimoto's encephalopathy

In 1966 Brain et al. described a 49-year-old man with Hashimoto's thyroiditis who presented with stroke-like episodes and subsequently delirium. The patient did not respond to prednisone, but eventually recovered, leading Brain to suggest that autoimmune mechanisms might be responsible. Since that time, there have been many further cases reported in the literature of Hashimoto's encephalopathy. The term Hashimoto's encephalopathy is used to describe an encephalopathy of presumed autoimmune origin characterized by high titres of antithyroid peroxidase antibodies. Hashimoto's encephalopathy is more common in women than in men. It has been reported in paediatric, adult and elderly populations throughout the world. The clinical presentation may involve a relapsing and remitting course and include seizures, stroke-like episodes, cognitive decline, neuropsychiatric symptoms and myoclonus. Thyroid function is usually clinically and biochemically normal. It is likely that antithyroid antibodies are not pathogenic, but titres can be a marker of treatment response. Pathological findings can suggest an inflammatory process, but features of a severe vasculitis are often absent.

Steroid-responsive nonvasculitic autoimmune inflammatory meningoencephalitic syndrome

Caselli RJ in 1999 reported five patients, age 54 to 80 years, presented between 3 weeks and 18 months after symptomatic onset of progressive cognitive decline, psychosis, and unsteady gait that proved to be due to a steroid-responsive nonvasculitic autoimmune inflammatory meningoencephalitic syndrome.

Limbic encephalitis (LE)

Main article: Limbic Encephalitis

The term limbic encephalitis (LE) was originally coined by Corsellis in 1968, present with the subacute onset of episodic memory impairment, disorientation and agitation, commonly associated with seizures, hallucinations, sleep disturbance and histological evidence of medial temporal lobe inflammation. Signal changes in the medial temporal lobes or hippocampi are frequently found on MRI. Its association with lung cancer and Hu antibody, Ma2 with testicular tumors and CRMP5/CV2 in patients with thymomas. Anti-NMDA-receptor encephalitis and its association with teratoma was published in 2008 by Josep Dalmau. There may be improvement after treatment of the primary tumor, but in general the prognosis of paraneoplastic limbic encephalitis is poor. A few cases of non‐paraneoplastic limbic encephalitis have been described.

Paraneoplastic Limbic Encephalitis (PLE)

Paraneoplastic limbic encephalitis (PLE) is a disorder characterized by personality changes, irritability, depression, seizures, memory loss and sometimes dementia.The diagnosis of PLE required neuropathological examination or the presence of the four following criteria: (i) a compatible clinical picture; (ii) an interval of <4 years between the development of neurological symptoms and tumour diagnosis; (iii) exclusion of other neuro-oncological complications; and (iv) at least one of the following: CSF with inflammatory changes but negative cytology; MRI demonstrating temporal lobe abnormalities; EEG showing epileptic activity in the temporal lobes.

Table

Paraneoplastic antibodies associated with limbic encephalitis

Antibody	Syndrome	Cancer
Hu	Limbic encephalitis, encephalomyelitis	SCLC, other
Ma2	Limbic, hypothalamic,a and brainstem encephalitis	Testis, lung, other
CV2/CRMP5	Limbic, striatal encephalitis (chorea), cerebellar ataxia, peripheral neuropathy, uveitis	SCLC, thymoma
Amphiphysin	Limbic encephalitis, stiff-person syndrome	Breast, SCLC
NMDA	Limbic encephalitis,	Teratoma of ovary
Anti-AMPAR	Limbic encephalitis	Lung, thymoma, breast, ovarian teratoma

Non Paraneoplastic Limbic Encephalitis (NPLE)

History

Mori M in 2002 reported a 21-year-old woman subacutely developed memory loss subsequent to gastroenteritis. Brain MRI with gadolinium enhancement showed symmetric involvement of the amygdala. The CSF was acellular with increased protein level. There was no evidence suggestive of neoplasm or viral infection. Combined treatment with plasmapheresis and immunoglobulin improved her clinical symptoms and lessened abnormalities manifested in the MRI. He suggested the presence of immune-mediated limbic encephalitis without association with neoplasms or infections. Similar case in an elderly man was presented with steroid response in 2003. Subacute onset partial seizures with recent memory and no evidence of underlying malignancy was recognized as limbic encephalitis unrelated to neoplasm.

Clinical Feature

Age: Children, Young Adult, Elderly

Sex: Both

Onset: Subacute

Clinical features NMDA Ab related patients in adult shows;

• Early features of higher cognitive dysfunction, confusion, behavioural changes, amnesia, dysphasia. Psychiatric: hallucinations, psychotic, agitation, depressive, anxiety, obsessive. Seizures: generalized, complex partial, simple partial.
• Late features: Spontaneous reduction in conscious level, Movement disorder: choreoathetoid (orofacial, upper limbs, lower limbs), parkinsonian, rigidity, myoclonus, oculogyric crises, opisthotonus, startle. Dysautonomia : tachy/brady-cardia, hyperhidrosis, persistent pyrexia, central hypoventilation, labile/high blood pressure, hypersalivation, pseudoobstruction, cardiac asystole .

NMDA Ab related patients in children and adolescent.

Commonly

• Behavioral or personality change, sometimes associated with
• Seizures and
• Sleep dysfunction;
• Severe speech deficits on admission
• Stereotyped movements,
• Autonomic instability
• Hypoventilation

Rarely

• Dyskinesias or dystonia;

Other Cases have similar presentation

• Disorientation,
• Hallucinations
• Confusion
• Memory loss
• Seizures: Partial temporal lobe. Pilomotor Status epilepticus
• Relative absence of cerebellar and brainstem sings
• Post partum psychosis
• Dyskinesias

Diagnosis

Antibody test in serum and CSF

1. Voltage‐gated potassium channel antibodies (VGKC‐Abs)
2. GluRepsilon2 (NR2B)
3. Glutamic acid decarboxylase (GAD).
4. Anti-NMDAR Ab most common in children unrelated to tumor.

Neuro Imaging

MRI: medial temporal lobe signal change bilateral hippocampal lesions, with signals that were hypointense in IR sequences and hyperintense in FLAIR.

Treatment

Immunotherapy with steroid and plasmapherasis, IVIG.

Prognosis

Variable following immunotherapy with partial to excellent recovery.

Chronic sequelae due to hippocampal sclerosis and chronic epilepsy is also reported.

Post herpes simplex NMDA antibody encephalitis

NMDAR Ab Encephalitis Following Herpes Simplex Virus Encephalitis Some children and adults with herpes simplex virus (HSV) encephalitis and subsequent relapses characterized by choreoathetosis in children and behavioral/psychiatric features in adults were found to have NMDAR Abs without HSV reactivation, they improved with immunotherapy.

Morvan's syndrome

Main article: Morvan's syndrome

History

In 1890, Morvan described a patient with myokymia (muscle twitching) associated with muscle pain, excessive sweating and disordered sleep Morvan's fibrillary chorea (MFC). The course was severe and the patient died 5 weeks after onset. A similar condition characterized by widespread myokymia and cramping, but without overt CNS involvement has since been described and is now referred to as Isaacs' syndrome (1961) and neuromyotonia (NMT) in 1965. Acquired NMT is thought to be autoimmune in a high proportion of cases. It can be associated with thymoma, and antibodies to voltage-gated K+ channels (VGKCs) are present in a proportion of patients. Although anti-VGKC antibody negative cases of Morvan's syndrome have been reported in the literature, it is possible that, in these cases, the antigenic components are yet to be formally identified.

Pathogenesis

Mice injected with NMT immunoglobulins have prolonged neuronal action potentials and increased neurotransmitter release. MFC, or Morvan's syndrome, is NMT with overt CNS involvement. It is probably also autoantibody-mediated but the nature of the CNS dysfunction and the targets for the antibodies are not clear.

In brain tissue regions including the hypothalamus, raphe, and locus coeruleus, commercial antibodies to LGI1 bound to neuronal cell bodies including the antidiuretic hormone-secreting and orexin-secreting hypothalamic neurons, whereas CASPR2 commercial antibodies bound more often to the neuropil. MoS antibodies bound similarly, but there was evidence of additional antibodies in some sera that were not adsorbed by LGI1- or CASPR2-expressing cells and bound to mouse Caspr2(-/-) tissue.

Clinical features

• Male (93%)
• Neuromyotonia (100%),
• Neuropsychiatric features (insomnia 89.7%, confusion 65.5%, amnesia 55.6%, hallucinations 51.9%),
• Dysautonomia (hyperhidrosis 86.2%, cardiovascular 48.3%),
• Neuropathic pain (62.1%)
• Associated tumors thymoma in (41.4%),

Investigation

MRI Brain: shows only evidence of small vessel disease, and normal in 92% of patients.

EEG: Nonspecific slow wave abnormality. Polysomnography shows complete absence of sleep.

Antigenic Source: VGKC-complex antibodies were present in 23 of 29 (79%), CASPR2, LGI1 antibodies, or both, CASPR2 antibodies were generally higher titer than LGI1 antibodies and associated with thymoma. LGI1 antibodies were associated with serum hyponatremia.

Treatment

Immunosuppressive therapies, encompassing corticosteroids, azathioprine, methotrexate and more recently, rituximab, are the mainstay of therapy. Other treatments include PE, IVIG, and thymectomy. Patients reportedly exhibited a heterogenous response to immunomodulation.

Antiepileptics can be used for symptomatic relief of peripheral nerve hyperexcitability. . Indeed, some patients have exhibited a spontaneous remission of symptoms.

Prognosis

Prognosis is poor, however, current analysis suggests that those associated with thymoma, benign or malignant, show a less favorable prognosis (CASPR2 Ab positive).

Autoimmune antibodies associated neurological syndromes (AAANS)

N-Methyl D-aspartate receptor (NMDAR, NR1, NR2)

Main article: Anti NMDA receptor Encephalitis

N-Methyl D-aspartate receptor (NMDAR) Ab encephalitis is the most common Ab-mediated autoimmune encephalopathy. It was first described in 2005 as a paraneoplastic syndrome associated with ovarian teratomas in young women and the antigenic target was determined in 2007, associated with antibodies against NR1 or NR2 subunits of the NMDA receptor. Irani et al. in 2010 presented NMDAR Ab encephalitis in a predominantly non-paraneoplastic disorder of both sexes.

Epidemiology

Most common cause of autoimmune encephalitis after acute demyelinating encephalitis in England. More than 500 cases have been reported in literature till 2013. In California Encephalitis Project it was found >4 times as frequently as herpes simplex virus type 1 (HSV-1), varicella-zoster virus (VZV), and West Nile virus (WNV). Among patients with first-onset schizophrenia incidence varies between 6-10%.

• Age- frequently 5–76 years, Median age of patients was 23 years
• Sex - 80% Female

Clinical Features

Prodrome

About 70% of patients have prodomal symptoms consisting of headache, fever, nausea, vomiting, diarrhoea, or upper respiratory-tract symptoms.

Syndrome

Within a few days, usually less than 2 weeks patients develop

• Behavioral disturbance: agitation
• Auditory and visual hallucinations,
• Delusions
• Psychosis
• Amnesia,
• Seizures,
• Dyskinesias, Catatonia, orolingual dyskinesias and stereotypic movement
• Autonomic dysfunction, and
• Decreased level of consciousness often requiring ventilatory support.

Antibody

The main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit. All had serum/cerebrospinal fluid antibodies that predominantly immunolabeled the neuropil of hippocampus/forebrain, in particular the cell surface of hippocampal neurons, and reacted with NR2B (and to a lesser extent NR2A) subunits of the NMDAR. NR2B binds glutamate and forms heteromers (NR1/NR2B or NR1/NR2A/NR2B) that are preferentially expressed in the adult hippocampus/forebrain

Tumor associated

Ovarian teratoma

Treatment

Treatment included first-line immunotherapy (steroids, intravenous immunoglobulin, plasmapheresis), second-line immunotherapy (rituximab, cyclophosphamide), and tumour removal.

Prognosis

Most patients recovered or had mild deficits and some had severe deficits or died.It may take up to 18 months for improvement was associated with a decrease of serum antibody titres. Untreated patients had high mortality (25%).

Voltage-gated potassium channel antibody syndromes

The voltage-gated potassium channel (VGKC) complex Abs are the second most commonly identified Abs in CNS Ab-mediated diseases, but the clinical spectrum and treatment responses are very different from those of the NMDAR Ab encephalitis. The clinical spectrum includes both central and peripheral nervous system disorders

History

VGKC complex Abs were first described in association with neuromytonia (NMT) or Isaac’s syndrome. VGKC complex Abs were found in around 40% of patients with NMT and then more frequently and at higher levels in patients with NMT associated with dysautonomia and CNS disturbance including insomnia and limbic dysfunction, which is usually called Morvan’s syndrome (MoS), and in a form of nonparaneoplastic limbic encephalitis (LE). Although these Abs were initially identified by immunoprecipitation of radioactive dendrotoxin-labeled VGKCs in digitonin-solubilized mammalian brain homogenates, further evidence indicated that they bind to protein components of the VGKC complex rather than to the VGKC itself; their identification requires Ag-specific cell-based assays.

Pathogenesis

The VGKC complex is composed of Kv1 subunits and other proteins that are tightly complexed with the Kv1 subunits in the nerve membrane. They are widely expressed in the nervous system, particularly at the juxtaparanodes of the nodes of Ranvier, at peripheral motor nerve, and perhaps sensory terminals, and in central synapses. Because opening of the VGKC following each action potential leads to repolarization of the membrane, VGKCs regulate neuronal activity throughout the nervous system.

In some patients VGKC Abs are detected by radioimmunoassay, in the absence of LGI1, CASPR2, or contactin 2 Ab specificity. In general, high titers (usually > 400 pM) are more frequently associated with defined clinical phenotypes (mainly LE, but also peripheral nerve hyperexcitability (PNH), seizures, or MoS), whereas low titers of Abs can be found in patients with either or both CNS and PNS syndromes but are also detected in patients without a clear immune-mediated phenotype. It is possible that, in these cases, the Abs bind to intracellular targets on the solubilized VGKC complex.

Potassium channel (KIR4.1): "Dipeptidyl-peptidase-like Protein-6 is a protein associated with another VGKC, Kv4.2, that is responsible for regulating firing rates of action potentials in dendrites in the central and peripheral nervous system.

VGKC antibodies spectrum

1. The main targets for the Abs are LGI1, typically associated with LE, and a specific focal epilepsy, faciobrachial dystonic seizures (FBDS). In around 20–40 % of patients with LGI1 Abs a specific seizure type can precede the occurrence of full-blown LE . These events have been described as “tonic seizures”, or FBDS, and consist of brief and very frequent involuntary movement with dystonic features involving mainly the arm, the ipsilateral side of the face, and, less frequently, the leg. The response to routinely used anticonvulsant drugs is usually poor, but a dramatic reduction or complete resolution of the FBDS can be obtained with oral steroids. Irani et al. described a prospective cohort of 10 patients with FBDS, where the development of cognitive impairment was only present in patients who did not receive immunotherapy, suggesting that early treatment can result in a better recovery and sometimes prevent progression to encephalopathy.
2. Contactin-associated protein like (CASPR2), associated with a broader spectrum of central and peripheral nervous system disorders such as LE, NMT, or a combination of the two (MoS).
3. A third antigen, contactin 2, has been identified, usually in patients with concomitant anti-LGI1 or anti-CASPR2 Abs and with no specific phenotype, suggesting an unclear clinical relevance.
4. Potassium channel (KIR4.1) Abs to dipeptidyl-peptidase-like protein-6 were initially identified in patients with a form of LE associated with gastrointestinal dysmotility (due to the involvement of the myoenteric plexus), sleep disturbances, cognitive and psychiatric manifestations, and dysautonomic features, and subsequently in a disease presenting with hyperekplexia, trunk rigidity, and cerebellar ataxia

Clinincal features

Age: Adult and Elderly

Sex: Both

Onset : Subacute

Behavior change

Memory loss, confabulation

Confusion and disorientation

Hallucinations

Dyssomnia

Seizures focal and generalized, myoclonic

Extrapyramidal dysfunction

Brainstem/cranial nerve dysfunction

Dysautonomia

Neuromyotonia

Peripheral nerve dysfunction

Hyponatreamia

Investigation

MRI Brain: Medial temporal T2 hyperintense signal changes in most cases. and atrophy on followup.

CSF: Mild pleocytosis and raised proteins and negative HSV.

Antibody: Elevated VGKC-Abs in CSF and Serum

EEG: Nonspecific background slowing and frontotemporal sharp waves.

Associated Tumors: 18 carcinomas, 5 adenomas, 1 thymoma, and 3 hematologic malignancies.

Associated autoimmune disease: thyroiditis 21%, type 1 diabetes mellitus 11%.

Treatment

Immunotherapy : Steroid, Plasmapheresis, IVIG.

Prognosis

Delayed recovery with immunotherapy. Marked recovery in 50%.

AMPAR (GluR1, GluR2) antibody syndrome

Anti–α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)are a subgroup of ionotropic glutamate receptor mainly present in excitatory synapses of the CNS. Abs against the extracellular domains of AMPA subunits GluR1 and GluR2 were associated originally with a particularly aggressive form of LE, often accompanied by the presence of a tumor.

Clinical features

• Age: Median age was 62 years (range 23–81; 14 female)
• Common
  • Limbic encephalitis (LE),12 (55%)
  • Limbic dysfunction along with multifocal/diffuse encephalopathy, 8 (36%)
• Rare
  • LE preceded by motor deficits
  • Psychosis with bipolar features.

Associated turmors: lung, thymoma, breast, ovarian teratoma (64%)

Treatment

Immunotherapy with steroid, relapse rituximab and/or cyclophosphamyde.

Prognosis

5 had good response to immunotherapy and tumor therapy, 10 partial response, and 6 did not improve. Eventually 5 patients died; all had a tumor or additional paraneoplastic symptoms related to onconeuronal antibodies. Coexistence of onconeuronal antibodies predicted a poor outcome.

Glycine receptor antibody syndrome

Pathogenesis: Abs directed against the α1 subunit of the glycine receptor (GlyR)

Clinical features

Variants of stiff person syndrome

• progressive encephalomyelitis,
• Rigidity,
• Myoclonus, stimulus-sensitive spasms, hyperkeplexia,
• Autonomic disturbances, and
• Brainstem disorders.
• Isolated Optic neurits
• Focal seizure in Adult

Treatment

Acombination of IVMP, PLEX, and IVIg followed by oral prednisolone. Relapsed required prolonged immunosuppression with MMF, AZA, or cyclophosphamide.

Prognosis

Improves with immunotherapy and complete resolution of clinical symptoms.

Dopamine 2 receptor antibody syndrome (D2RA)

History

Sydenham's chorea is the foremost classic autoimmune basal ganglia disorder. Possible autoimmune mechanism for Encephalitis Lethargica with Parkinsonian syndrome has been suggested. The evidence for an autoimmune disorder is less clear for paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). An autoimmune subgroup may exist in Tourette’s syndrome, although results remain controversial. Autoimmune movement disorder with basal ganglia encephalitis associated with D2RA have found recently.

Pathogenesis

D1- and D2-class receptors have high expression in basal ganglia, for example striatum (caudate–putamen), but also in cortex, hippocampus and substantia nigra. Modulation of D2R expression in the basal ganglia has been associated with schizophrenia, depression and movement disorders. D2R is intimately linked to the control of movement and behavior e.g. myoclonus dystonia is associated with D2R gene mutations. Movement and psychiatric disorders associated with D2R antibody are biologically plausible as D2R is intimately linked to the control of movement and behavior.

Clinical features

Movement Disorder

• Dystonia
• Parkinsonism
• Chorea
• Ocular flutter
• Motor tics

Psychiatric Symptoms

• Agitation
• Emotional lability
• Psychosis
• Depression

Associated symptoms

• Encephalopathy
• Sleep disorder
• Reduced consciousness
• Mutism

Diagnosis

Based on syndrome with focal or diffuse neurological dysfunction associated with fever. Inflammatory lesion in MRI and CSF pleocytosis. EEG signs of encephalitis.

Treatment

Immunotherapy

Prognosis

Commonly monophasic illness, few had relapse after improvement. Persistent neurological deficit were recorded before immunotherapy was given in historical cases.

GABA Receptor Ab Syndrome

History

High titres of serum and CSF GABAA receptor antibodies are associated with a severe form of encephalitis with seizures, refractory status epilepticus, or both. Another paper described 40 patients with Abs of the IgG and IgM subclasses targeting the α1 and γ2 subunits of the GABAA receptor.

GABABR is a protein widely distributed in the brain and located both pre- and postsynaptically. Genetic alterations of the receptor are associated with epilepsy and cognitive impairment, and Abs against the B1 subunit are found in patients with LE and, rarely, ataxia, 50% of whom will have a small-cell lung carcinoma. Encephalitis associated with anti-γ-aminobutyric acid-B (GABAB) receptor antibodies has been identified recently.

Clinical features

GABAb Ab syndrome has a clinical triad of confusion, memory changes, seizure, Rarely ataxia, status epilepticus and opsoclonus-myoclonus syndrome (OMS).

GABAa Ab syndrome has most common presenting features were seizures (47%), memory impairment (47%) with confusion or disorientation (27%), or psychiatric features (33%) with hallucinations (33%) or anxiety (27%). Refractory status epilepticus.

Tumor association

• Lymphoma in few cases of GABAa Ab syndrome
• Small-cell lung cancer in 50% of GABAb Ab syndrome.

Diagnosis

MRI were normal or nonspecific in most cases.

CSF examination was also not informative.

Treatment

The administration of immunotherapy, in association with chemotherapy or tumor removal, .

Prognosis

A complete recovery following immunotherapy and tumor removal. Untreated cases died within few months of onset. Some patients have a poor outcome despite sustained immunosuppression, but that is often related to tumor progression or associated with the presence of Abs directed against intracellular Ags such as GAD Abs or amphyphysin Abs, which can reflect the involvement of an additional cytotoxic T-cell mechanism in the progression of the disease.

Metabotropic glutamate receptor antibody syndrome

Metabotropic glutamate receptors belong to a large family of cell-surface receptors that transmit signals into the cell by coupling to guanine nucleotide-binding proteins (G proteins) in the cytoplasm.

Subacute cerebellar ataxia

Metabotropic Glutamate Receptor type 1 Ab (mGluR1) syndromes is rare and recently described associated with few cases with subacute cerebellar ataxia associated with Hodgkin lymphoma in 2000.

Subsequently a non paraneoplastic syndrome, was described and the disease was stabilized after a course of intravenous immunoglobulins and continuous mycophenolate mofetil treatment during a follow-up of 40 months.

Ophelia syndrome

More recently (2011), Abs directed to the mGluR5 Abs were identified in 2 patients with limbic encephalopathy and Hodgkin's lymphoma, a combination known as Ophelia syndrome. Hippocampus neuron mGluR5, a receptor involved in processes of learning and memory.

Ophelia syndrome was characterized by

1) the epitopes are in the extracellular domain of the receptor, as shown by patients' antibody binding to the surface of live neurons;

2) the antibodies specifically react with mGluR5, as demonstrated by the abrogation of reactivity with brain of mGluR5-null mice and lack of cross-reactivity with mGluR1; and

3) the neurologic disorder is reversible.

In both cases prompt tumor treatment (excision or chemotherapy) was performed, and 1 patient also received steroids, resulting in complete regression of the symptoms.

IgLON5 Ab Syndrome

In 2014, a novel syndrome with sleep disorders (parasomnia and breathing dysfunction), gait instability, and brainstem symptoms was described in 8 patients in association with surface Abs to the neuronal cell adhesion protein IgLON5. Neuropathological investigations in 2 patients identified tau aggregates in the tegmentum of the brainstem and in the hypothalamus that could not be classified within any known tauopathy, suggesting a possible neurodegenerative etiology of the disease. Moreover, despite immunosuppressive treatments including steroids, IVIg, cyclophosphamide, and rituximab, only 1 patient showed some improvement. Whether the Abs are a primary or secondary element in the disease development needs to be clarified.

See also

• Sydenham's chorea
• Encephalitis lethargica
• Limbic encephalitis
• Hashimoto's encephalopathy
• Paraneoplastic encephalitis
• Rasmussen encephalitis
• Systemic lupus erythematosus
• Behcet's disease
• Morvan's syndrome

External links

• Autoimmune Encephalopathy