62 Journal of The Association of Physicians of India ■ Vol. 65 ■ February 2017 REVIEW ARTICLE Autoimmune Encephalitis: An update Satish Khadilkar1, Girish Soni2, Sarika Patil3, Abhinay Huchche4, Hinaben Faldu 5 Introduction E ncephalitis (brain inflammation) is often thought to be mediated by infections (e.g. viral). 1,2 With the advances in molecular diagnostics, new immunological markers (antibodies) are being discovered in patients presenting with encephalitic syndromes. Thus, research has evoked interest in the ‘immune theory’ of encephalitis. This group of disorders is appealing to clinicians because of the favourable response to immunotherapy viz a viz infectious encephalitis where limited pharmacotherapy is available for most of the viral agents. Va r i o u s s y n d r o m e s o f autoimmune encephalitis have been described and many more are expected with the advent of newer biomarkers. The clinical syndrome comprises a complex of encephalopathy, cognitive disturbances, mood/personality changes, seizures and movement disorders. Each of these can be the presenting manifestation, opening up a wide differential diagnosis, often delaying the diagnosis and therapy. The purpose of this review is to update recent information on autoimmune encephalitis. Table 1: Clues for diagnosis of autoimmune encephalitis • Subacute onset of memory impairment (short-term memory loss), encephalopthy or psychiatric symptoms • At least 1 of the following: Clinical Clues to the Diagnosis of Autoimmune Encephalitis Important clinical clues to suspect autoimmune encephalitis are subacute onset, fluctuating course, mood and behaviour changes, cognitive dysfunction, seizures, dyskinesiae and tremors. 3 This may be supplemented by T2 hyperintensity on MRI (most commonly in the mesial temporal region), inflammation in CSF, hypometabolism on functional imaging and confirmation comes with detection of specific autoantibody. (Improvement after immunotherapy may be diagnostically informative). However, obtaining autoantibodies Fig. 1: Diagram showing cell surface antigens (NMDAR, AMPAR, LGI1, CASPR2 etc.) intracellular synapse-related (GAD, ampiphysin) and intracellular (anti-Hu, anti-CRMP5, anti-Yo etc.) NMDA R-N methyl D Aspartate receptor,VGKC- voltage-gated potassium channel complex –complex, LGI1- Leucine-rich Glioma inactivated, CASPR2Contactin-associated protein-2, AMPA-R- Anti-alpha-amino3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, Gly R- glycine receptor, mGluR5-metabotropic glutamate receptor 5, GAD- Glutamate acid decarboxylase • Focal neurological deficits • Unexplained seizures • CSF pleocytosis (white blood cell count >5 cells per mm3) • MRI features suggestive of encephalitis. • Exclusion of alternative causes 1 Professor of Neurology, Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra; 2Asso. Professor of Neurology, 3Neurology Registrar, Grant Government Medical College and Sir JJ Group of Hospitals, Mumbai, Maharashtra; 4Consultant Neurologist, Bombay Hospital Institute of Medical Sciences, Mumbai; 5Neurology Registrar, Grant Government Medical College and Sir JJ Group of Hospitals, Mumbai, Maharashtra Received: 10.09.2016; Accepted: 11.10.2016 Journal of The Association of Physicians of India ■ Vol. 65 ■ February 2017 Table 2 : Diagnostic clues: anti-NMDA receptor encephalitis 1. Rapidly progressive following symptoms: Abnormal behaviour or cognitive dysfunction Decreased level of consciousness Speech dysfunction Seizures Movement disorder, especially oral dyskinesias Autonomic dysfunction or central hypoventilation 2. At least one of the following study results: Abnormal EEG (slowing, epileptiform activity or extreme delta brush) CSF pleocytosis or oligoclonal bands 3. Exclusion of other disorders 4. Accompanied by a systemic teratoma 5. IgG anti-GluN1 antibodies (Definite) urgently in resource poor settings may be challenging and waiting for response to immunotherapy may not be prudent, as some patients may need second line immunosuppressive treatment. Diagnostic clues are summarized in Table 1. neurologic syndromes, including cerebellar ataxia, opsoclonus/ myoclonus, encephalomyelitis and limbic encephalitis. Intracellular antigens are poorly responsive to immunotherapy. Well Characterized Autoimmune Encephalitis Syndromes Anti-NMDAR-encephalitis Anti-NMDAR-encephalitis is the most common autoimmune encephalitis 5 in which IgG antibodies against the GluN1 subunit of the NMDA receptor are present. It can affect all age groups, but is more common in children and young adults females. 6 The clinical presentation can be divided in to following stages. 1. Prodromal phase with infection; fever and headache 2. Early stage with psychosis, confusion, amnesia and dysphasia 3. Late stage (within 1–2 weeks) characterised by movement disorders (choreo-athetoid movements, stereotypy), autonomic instability, encephalopathy with hypoventilation. Some patients become mute and catatonic. Role and Types of Autoantibodies Three groups of against intracellular, synapse-related and antigens have been (Figure 1). antibodies intracellular cell surface recognized Antibodies to neuronal surface antigens are often directed at conformational epitopes. Antibody binding disrupts the synaptic interaction and plasticity of these epitopes and prevents the active expression of these receptors. Antibody heterogeneity regarding epitope results in multiple con cu r r e n t pa thop h ysiological effects of the antigen-antibody binding which may explain the large clinical variations seen in patients. Disruption for long periods tends to render irreversible damage, while only functional damage may be reversible 4 Intracellular antigens are primarily associated with paraneoplastic Other clinical presentations are 1. Au t o i m m u n e r e f r a c t o r y epilepsy 2. Schizophrenia like symptoms 3. Demyelinating disorder 4. Patient with herpes simplex encephalitis with anti NMDA receptor antibodies Tu m o u r s a r e p r e s e n t i n 40-50% in women older than 18 years. Most common tumour is ovarian teratoma 6. Other types of malignancies (small-cell lung, pancreatic, and breast cancer1 and Hodgkin’s lymphoma) have occasionally been identified. Some patients do not have an underlying neoplastic disease7. Nevertheless, all patients should undergo extensive tumour screening, at presentation 63 and at yearly intervals. 5 Better outcomes have been reported with early resection of tumour. MRI brain is often normal. If abnormalities are present, they are seen as T2, FLAIR hyperintense lesion either in limbic cortex, in the brainstem, basal ganglia o r t h e c e r e b e l l u m . 6,7 M o d e r a t e lymphocytic pleocytosis can be seen in CSF.7 NMDA receptor antibodies are synthesized both systemically and intrathecally. Upto 15% of patients do not have serum antibodies, but do have positive CSF antibodies. 10 EEG shows widespread theta-delta a c t i v i t y s u g g e s t i ve o f d i f f u s e cerebral dysfunction. Also a particular pattern is observed; extreme delta brush (slow waves with overriding fast beta activity) in 30% of patients. 11,12 Detection of this unique pattern should prompt consideration of anti NMDA receptor encephalitis. 11 Their presence also suggests a more prolonged disease course. 11 About 50% patients treated with first line immunotherapy using steroids, intravenous immunoglobulins, plasmapheresis and tumour removal show improvement within 3-4 weeks. 8 Patients who do not show improvement to first line therapy can potentially show good response to second line immunotherapy like rituximab, cyclophosphamide and others. 8 Some experts recommend comprehensive immunotherapy that consists of giving rituximab, IvIg or PE and methylprednisolone up front, all at the same time to alter the natural course of disease and to prevent relapse. 9 Table 2 gives the approach to anti NMDR encephalitis. Case Vignette: 17 year female presented with abnormal fluctuating behaviour (paranoid ideation) and focal seizures over 6 weeks. After 1-2 weeks, she developed abnormal posturing of the right hand with involuntary perioral movements, refractory status epilepticus and mutism. There was no history of Routine investigations including anti TPO antibody level were within normal limits. MRI brain and CSF studies were also normal. Her EEG showed generalised theta-delta range slowing with “delta brush” and focal epileptiform discharges as well (figure 1). CSF antiJournal of The Association of Physicians of India ■ Vol. 65 ■ February 2017 64 NMDA receptor antibody was positive. Figure 2. EEG showing generalised theta-delta range slowing with serrated appearance Fig. 2: EEG showing generalised theta-delta range slowing with serrated of delta waves (duefast to overriding fast beta activity)area; in frontal of deltaappearance waves (due to overriding beta activity) in frontal representing extreme area; representing extreme delta brush delta brush autoimmune encephalitis. fever, headache, myoclonic jerks, visual complaints, weight loss LEARNING POINTS • Delta Brush on EEG is an Fig. 3: MRI brain was suggestive of or any systemic complaints. At important marker and should T2 and FLAIR hyperintense the time of Young admission, was femaleshe presenting with psychiatric symptoms can have be looked for in every patient of autoimmunesignal in bilateral mesial in encephalopathy with status temporal lobe suspected NMDA encephalitis. encephalitis. epilepticus, and had pyramidal Delta Brush on EEG is an important marker and shouldyield be looked for in every • Rituximab can increase in signs with right upper limb dystonic 40-50% of patients can have normal non-responders. patient of suspected NMDA encephalitis. posturing and perioral dyskinetic MRI. 15 The CSF is usually normal, VGKCComplex antibodies mediated m o v e m e n t sRituximab . D u r i n gcan h oincrease s p i t a l yield in non-responders. although mild inflammatory encephalitis stay, she developed autonomic changes may be present. EEG Diseases associated with VGKC B. VGKC- Complex antibodies encephalitis disturbances, respiratory distress mediated usually shows inter-ictal complex antibodies include for which she was intubated and epileptiform activity or slowing Diseases associated with VGKC complex include epilepsy, l i mantibodies bic enceph a l i t i s , limbic e p i l e pencephalitis, sy, mechanically ventilated. over anterior or mid-temporal neuromyotonia/peripheral nerve region. Limbic Association with tumours Routine investigations including neuromyotonia/peripheral nerve hyper excitability and Morvan’s syndrome. hyper excitability and Morvan’s is very rare. Majority of patients a n t i T P O a n t i b o d y l e ve l we r e syndrome. Limbic encephalitis respond well to immunotherapies within normal limits. MRI brain is the most common syndrome such as steroids, plasma exchange, and CSF studies were also normal. form. 13 The antibodies directed and IvIg. These patients tend to Her EEG showed generalised thetaagainst proteins of the VGKChave a monophasic disease, but delta range slowing with “delta 15 complex include LGI1, CASPR2, 20% patients relapse. brush” and focal epileptiform and Contactin-2. 13 discharges as well (Figure 2). CSF Case Vignette: A 59 year Anti LGI1 associated encephalitis anti-NMDA receptor antibody was old Doctor was admitted with Anti LGI1 encephalitis presents positive. frequent left upper limb and facial w i t h m e m o r y l o s s , c o n f u s i o n , j e r k y i n v o l u n t a r y m o ve m e n t s She received a course of temporal lobe seizures, agitation, with fluctuating encephalopathy. intravenous methylprednisolone an d oth er psy chiat ric feat ures During hospital stay frequency (MPS) followed by intravenous evolving over several days or weeks of jerks increased to every 2-3 immunoglobulin’s (IvIg) but and predominantly affects elderly m i n u t e s . H e wa s a f e b r i l e a n d showed no signs of improvement. males. Some patients develop brief his routine haematological and Later on, weekly regime of tonic or myoclonic-like seizures 2 biochemical investigations and CSF rituximab (375mg/m ) was given. (also called facio-brachial dystonic studies were normal. MRI brain She improved significantly and seizures) that precede the memory was suggestive of T2 and FLAIR subsequently weaned off the 13 and cognitive deficits. Low serum hyperintense signal in bilateral ventilator. Presently she is on low sodium concentrations have been mesial temporal lobe (Figure 3). dosage of steroids and course of 13 reported in 60% patients. Rapid EEG showed diffuse generalised rituximab with regular monitoring eye movement sleep behaviour intermittent slowing (Figure 4). of CD 19 levels. disorder is common in these His anti-VGKC antibody- anti Learning Points patients. 14 MRI brain shows T2 LGI1 was strongly positive. He was • Young female presenting with and FLAIR hyper intensities in the given valproate, clonazepam and psychiatric symptoms can have mesial temporal lobes, but up to methylprednisolone [MPS] course Journal of The Association of Physicians of India ■ Vol. 65 ■ February 2017 65 Table 3: Clues for Diagnosis of Hashimoto’s encephalopathy • Encephalopathy with seizures, myoclonus, hallucinations, or strokelike episodes Fig. 5: EMG showing myokymic discharges Fig. 4: EEG showing intermittent theta-delta range slowing without much benefit. Hence was started on plasmapheresis and after 3 rd cycle, he showed significant reduction in jerks and confusion. While tapering steroids and AEDs, his facio-brachial jerks increased with worsening of sensorium. Since there was recurrence of symptoms, steroid sparing immunomodulator was added with short course of MPS and IvIg. Learning Points • Fasciobrachial jerks predominate and are early in clinical presentation. • Some patients of LGI1 R encephalitis may relapse and requires second line immunosuppression. Anti-CASPR2 Associated Encephalitis Patients with CASPR2 antibodies usually develop Morvan’s syndrome. This syndrome was first described in 1890 by Augustin Morvan as a syndrome associated with autonomic dysfunction and severe insomnia. 16 Patients with Morvan’s syndrome present with a subacute onset of peripheral nerve hyperexcitability (PNH), dysautonomia, and encephalopathy with marked insomnia. 17 More than half of patients complain of pain, which could be of a neuropathic nature or manifest as arthritis or myalgia. Dysautonomia leads to variable hyperhidrosis, cardiac arrhythmias, haemodynamic disturbances, impotence, constipation, urinary problems, excess salivation, and lacrimation.18-20 Rare cases of isolated limbic encephalitis or PNH have been reported. Patients may have other coexisting immune mediated disorders such as myasthenia gravis with antiacetylcholine (AChR) or muscle-specific kinase (MuSK) antibodies. 21 A high proportion of the VGKC-complex antibodies in Morvan’s syndrome are directed against CASPR2, but some patients have LGI1 antibodies. 13 MRI brain is often normal. Thymoma is most common tumour associated with Morvan’s syndrome. Some patients recover spontaneously, 22 but majority of patients show good response to immunotherapy. Case Vignette: An 18 years old boy was admitted with 4 weeks history of bilateral lower limb cramps, insomnia and flickering m u s c l e m o ve m e n t s o ve r a l l 4 limbs even in sleep. Examination ahowed postural drop in blood pressure with myokymia in all 4 limbs and tremors of bilateral hand with involuntary movements of toes. EMG showed myokymia (Figure 5) with normal NCS. MRI brain, EEG and CSF study were normal. His anti VGKC antibody (CASPR 2) was strongly positive, confirming the diagnosis of Morvan’s syndrome. There was no evidence of malignancy on PET CT. He was given iv MPS for 5 days followed by oral steroid and carbamazepine for myokymia. His cramps and sleep improved within few days with significant reduction in myokymia. Learning Points • Pa t i e n t s c a n p r e s e n t w i t h lower motor neurone features like cramps, neuromyotonia, insomnia , autonomic dysfunction without encephalopathy. • Malignancy is seen in only a proportion of patients. • Subclinical or mild overt thyroid disease (usually hypothyroidism) • Brain MRI normal or with non-specific abnormalities • Presence of serum thyroid (thyroid peroxidase, thyroglobulin) antibodies • Absence of well characterised neuronal antibodies in serum and CSF • Exclusion of alternative causes Hashimoto’s encephalopathy Hashimoto’s encephalopathy is a steroid responsive encephalopathy characterized by fluctuating or persisting altered sensorium and neurologic deficits associated with e l e va t e d b l o o d c o n c e n t r a t i o n s o f a n t i - t h y r o i d a n t i b o d i e s . 23,24 Antibodies associated with this condition include antithyroid peroxidase antibodies (antithyroid microsomal antibodies) and antithyroglobulin antibodies. 23 Based on the consistent and spectacular steroid response, the condition has been renamed as steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT). 23 The clinical presentation is of fluctuating or progressive encephalopathy, myoclonic jerks, seizures, stroke like episodes. It is important to bear in mind that the thyroidstimulating hormone levels can be normal in this disorder. CSF o f t e n s h o w s e l e va t e d p r o t e i n levels without pleocytosis. 25 EEG is usually abnormal showing generalized slowing. Triphasic waves, focal slowing, and epileptiform abnormalities may also be seen. MRI of the brain is often normal in 50% of cases, but can reveal subcortical white matter hyperintensities on T2-weighted or fluid-attenuated inversion recovery (FLAIR) imaging and brain atrophy. 24 Treatment includes high dose steroids. The neurological and psychiatric symptoms respond early to treatment, although EEG normalization takes some Presence of serum thyroid (thyroid peroxidase, thyroglobulin) antibodies 66 Absence well characterised antibodies in serum and CSF Journal of Theof Association of Physicians of India ■neuronal Vol. 65 ■ February 2017 Exclusion of alternative causes antibody titre- > 1000 IU/ML. CSF time. Around 2-5% of patients Anti-gamma-aminobutyric acid studyaltered was normal. EEG showed m a yyear n o t old r e s pfemale o n d t o spresented teroids, B receptor (GABA-B noticed R) encephalitis 65 with behavior since 1 month. Relatives that intermittent generalized slowing in whom azathioprine, IvIg or affects men and women similarly andrelatives, MRI brain was of plasmapheresis be used with close a n d pmutism r e s e n t w and i t h t hsphincter e typical she was notcanrecognizing andsuggestive had fluctuating bilateral white matter T2/FLAIR good results. 26 Table 3 lists the clues features of limbic encephalits 27,28 hyperintense signal (Figure 6). disoriented and prominent to the diagnosis. visual hallucinations. They incontinence, On examination she was with seizures. poor attention She was treated with inj MPS 1gm frequently have underlying small Case Vignette: 65 year old female iv for 5 days followed by oral cell lung carcinoma. Cerebellar presented behavior span. Shewith wasaltered moving all 4 limbs and alland reflexes were brisk. Hemogram and routine steroid taper levothyroxine ataxia and opsoclonus–myoclonus since 1 month. Relatives noticed replacement. She responded syndrome can co exist.27,28 The brain that she was nottests recognizing close electrolytes biochemical including were normal. Erythrocyte was dramatically to treatment and was MRI sedimentation is often abnormalrate showing r e l a t i ve s , a n d h a d f l u c t u a t i n g cognitively normal within a week. unilateral or bilateral medial mutism and sphincter incontinence, 60mm at 1 hr with normal serum ammonia level. T366.5 ng/dl [N=70-204], T4-signal 3.77 temporal lobe FLAIR/T2 Learning Points visual hallucinations. On consistent with limbic encephalitis examination she was disoriented • In elderly patients with altered microG/dl [N= 4.83-11.72], TSH – 7.82. AntiTPO antibody titre1000 CSF study and>CSF canIU/ML. show lymphocytic with poor attention span. She sensorium, one should consider pleocytosis. was moving all 4 limbs and all Hashimoto’s encephalopathy was normal. EEG showed intermittent MRI brainReceptor was suggestive of Encephalitis reflexes were brisk. Hemogram a f t e rgeneralized e x c l u d i n g a lslowing t e r n a t i veand Anti-GABA-A and routine biochemical tests c a u s e s , e ve n i n a b s e n c e o f Patient present with refractory bilateral white matter T2/FLAIR hyperintense signal. She was treated with inj MPS 1gm Itiv including electrolytes were normal. myoclonic jerks. seizures and status epilepticus. Erythrocyte sedimentation rate was is preceded by rapidly progressive, • Patients show dramatic 29 60mm at 1 hrfollowed with normal for 5 days byserum oral steroidresponse taper toand levothyroxine replacement. She responded severe encephalopathy. Majority steroids. a m m o n i a l e ve l . T 3 - 6 6 . 5 n g / d l of patients have extensive MRI Anti-GABA Receptor Encephalitis [N=70-204], T4- to 3.77treatment microG/dl [N= dramatically and was cognitively normal within a week. abnormalities on FLAIR and T2 Anti-GABA-B Receptor Encephalitis 4.83-11.72], TSH – 7.82. Anti- TPO imaging with multifocal corticalsubcortical involvement without contrast enhancement. No cancer association has been seen. Anti-AMPA Receptor Encephalitis Fig. 6: MRI brain showing bilateral T2 /FLAIR hyperintense signal A n t i A M PA - R e n c e p h a l i t i s predominantly affects middleaged women (median age 60 years) and patients present with subacute onset symptoms of limbic encephalitis associated with prominent psychiatric symptoms 30,31 Patients with antiA M PA - R - a n t i b o d y a s s o c i a t e d limbic encephalitis have a high Figure 6. MRI brain showing bilateral T2 /FLAIR hyperintense signal. Table 4 Demographic profile Antibody target Tumour association Response to immunotherapy Other charactristics Anti-NMDAR encephalitis Children and young women NMDAR (mainly NR1 subunit) Ovarian (or other) teratomas in ≤50% Responds well to early immunotherapies and early tumour removal but nonparaneoplastic cases can be chronic and tend to relapse EEG- extreme delta brush AntiLGI1- encephalitis Anti CASPR2Anti GABABRassociated encephalitis encephalitis Older men, Median age Adult males Median age 62 years 60 years VGKC-complexVGKC-complex GABABR1 associated associated LGI1 A CASPR2 Tumours are very rare. Thymomaprincipally, Thymoma and small-cell lung cancer. Lung Anti AMPAR-Ab encephalis. Middle aged women Often monophasic without need for continuing immunosuppression Responds to treatments but relapses common 60% develop hyponatremia Can be treatment Responds to responsive treatments or have spontaneous improvement, but prognosis confounded by tumour when present EMG- Myokymia Frequent coexisting autoimmune diseases GluR1/2 thymoma, lung, breast 56 Journal of The Association of Physicians of India ■ Vol. 65 ■ February 2017 Journal of The Association of Physicians of India ■ Vol. 65 ■ February 2017 67 Autoimmune encephali�s Predominant neuropsychiatric features Predominant neurological feature (Behavioural; personality change, psychosis, confusion, confabula�on,agita�on) Age of Onset Young Age Old Age An� NMDA An� AMPA autonomic dysfunc�on, stereotyped movements Epilepsy, Fasciobrachi al dystonia Ataxia. An� GABA R1 Epilepsy Hallucina�on, epilepsy,coma ) Anti VGKCv LGi 1 Cognitive decline with myoclonic jerks Neuromyotoni a with autonomic dysfunc�on and memory loss encephalo myeli�s with rigidity and myoclonus Hashimoto encephali�s An� VGKCCASPR2 Morvan’s Anti Glycine R encephalitis syndrome Algorithm 1: Clinical approach to autoimmune encephalitits tendency to relapse. 31 About 70% have an underlying tumor in the lung, breast, or thymus. 32 AMPA-R encephalitis patients respond well to immunotherapy and tumor treatment. r e s p o n s e s a n d l i m b s p a s m s . 35 These cases are mostly unrelated to cancer and patients often have good responses to immunotherapy. Table 4 summerizes the salient features of this group of conditions. neuropsychiatric symptoms usually preceded by intense diarrhea. 36 This syndrome is also characterized by trunk stiffness, hyperekplexia, marked cerebellar ataxia in few patients. 37 Disorders associated with GlyR antibodies Newer disorders Encephalitis with Antibodies to IgLON5 Anti-glyR antibody-related encephalitis patients presents with progressive encephalomyelitis with rigidity and myoclonus (PERM).33,34 They may also present with muscle stiffness, hyperactive startle Anti-DPPX Encephalitis The encephalitis associated with antibodies to dipeptidylpeptidaselike protein-6 (DPPX) was recently described, it predominantly affects adults (age 45–76 years). Patient present with prominent This is recently described disorder with antibodies to IgLON family member 5 has a median age of onset of 59 years. Patients develop abnormal REM and non REM sleep movements, and behaviours and obstructive sleep 68 Journal of The Association of Physicians of India ■ Vol. 65 ■ Februa Journal of The Association of Physicians of India ■ Vol. 65 ■ February 2017 Diagnosis (refer table no 1.) MRI brain- UL/BL Mesial temporal hyperintensi�es or subcor�cal hyperintensity with or without enhancement. EEG-Generalised or focal slowing and/or epilep�form discharges. CSF-Elevated protein, pleocytosis, abnormal oligoclonal bands. An�body tes�ng Acute Treatment IV MPS (1 gm daily for 5 days) OR IVIg (0.4mg/kg daily for 5days) OR Plasma exchange(severe a�ack, incomplete response to steroids) No Improvement Improvement IV rituximab( 375mg/m2 weekly for 4 weeks. OR IV cyclophosphamide 1gm iv monthly for 6 months Maintenance treatment Oral prednisolone taper over 4-6 months and consider Oral azathioprine OR Oral mycophenolate mofe�l OR IV rituximab (Monitor with CD 19 level) Algorithm 2: Management of autoimmune encephalitisencephalitis Algorithm 2 : Management of autoimmune discussion, immune mediated apnea. 38 Brain MRI, EEG, and CSF with cerebellar ataxia, limbic movements, and behaviours and clinical and management aspects of syndromes form an encephalitic studies and electromyography is encephalitis. The co-occurrence of 38 important group of modifiable often normal. Patients has limbic encephalitis and Hodgkin immune encephalitis. obstructive sleepusually apnea. Brain 1. Venkatesan neurological disorders. These areA, Tunkel AR, Bl aMRI, rapidly progressive course with lymphoma is known as Ophelia EEG, and CSF studies and the International Encepha being increasingly recognised due poor response to immunotherapy. syndrome. 39 electromyography is often normal. Case definitions, diagnos to availability of serum makers and Death can occur due to autonomic Algorithm 1 and 2 summarize the Patients usually has a and priorities in encepha have been better characterised in dysfunction. clinical and management of t h e a b o v e A s s e e naspects from r a pmGluR5 i d l y progressive course with the recent years. Thesestatement disorders of the internatio Anti immune encephalitis. discussion, immune m e d i various a t e d patterns of clinical have consortium. Clin Infect Dis poor response to immunotherapy. Patients with antibodies to the encephalitic syndromespresentations form an which correlate with Concluding Remarks 28. metabotropic Death c a n oglutamate c c u r d ureceptor e to important group of modifiable antibodies. Clinical suspicion and 5a have been reported to present 2. Kennedy PGE. Viral encep u t o n o m i c dysfunction. As seen from the above knowledge is neurological disorders. These are of these syndromes differential diagnosis, and Anti mGluR5 being increasingly recognised due Neurol Neurosurg Psychiat Patients with antibodies to the i15. to availability of serum makers and References Concluding Remarks Journal of The Association of Physicians of India ■ Vol. 65 ■ February 2017 important to the clinician as these are amenable to immunotherapy. 13. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Venkatesan A, Tunkel AR, Bloch KC, et al, for the International Encephalitis Consortium. Case defi nitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis 2013; 57:1114– 28. Kennedy PGE. Viral encephalitis: causes, differential diagnosis, and management J Neurol Neurosurg Psychiatry 2004; 75:i10i15. 14. Irani SR, Alexander S, Waters P, et al. Antibodies to Kv1 potassium channelcomplex proteins leucine-rich, glioma inactivated 1 protein and contactinassociated protein-2 in limbic encephalitis, M or van’s syndrome and acquired neuromyotonia. Brain 2010; 133:2734– 2748. Iranzo A, Graus F, Clover L, et al. Rapid eye movement sleep behavior disorder and potassium channel antibody-associated limbic encephalitis. Ann Neurol 2006; 59:178–81. 69 27. Hoftberger R, Titulaer MJ, Sabater L, et al. Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients. Neurology 2013; 81:1500–1506. 28. Jeffery OJ, Lennon VA, Pittock SJ, et al. GABAB receptor autoantibody frequency in service serologic evaluation. Neurology 2013; 81:882–887. 29. Petit-Pedrol M., Armangue T, Peng X, et al. Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterization of the antigen, and analysis of the effects of antibodies. Lancet Neurol 2014; 13:276– 286. 15. Irani SR, Buckley C, Vincent A, et al. Immunotherapy-responsive seizurelike episodes with potassium channel antibodies. Neurology 2008; 71:1647–48. 30. 16. Graus F, Boronat A, Xifro X, et al. The expanding clinical profile of anti-AMPA receptor encephalitis. Neurology 2010; 74:857–859. Tanaka, K. Recent update on autoimmune encephalitis/encephalopathy. Clin Exp Neuroimmunol 2014; 6:1759-1961 Walusinsk i O, Mor van HJA, (18191897), a little-known rural physician and neurologist. Rev Neurol (Paris) 2013; 169:2-8. 31. 17. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 2011; 10:63–74. Lancaster E, Martinex-Hernandez E, Dalmau J. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology 2011; 77:179–189. Lai M, Hughes EG, Peng X, et al. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol 2009; 65:424–434. 32. 18. Spinazzi M, Argentiero V, Zuliani L, Palmieri A, Tavolato B, Vincent A. Immunotherapyreversed compulsive, monoaminergic, circadian rhythm disorder in Morvan syndrome. Neurology 2008; 71:2008–10. Bataller L, Galiano R, Garcia-Escrig M, et al. Reversible paraneoplastic limbic encephalitis associated with antibodies to the AMPA receptor. Neurology 2010; 74:265–67. 33. 19. Josephs KA, Silber MH, Fealey RD, Nippoldt TB, Auger RG, Vernino S. Neurophysiologic studies in Morvan syndrome. J Clin Neurophysiol 2004; 21:440–45. Hutchinson M, Waters P, McHugh J, et al. Progressive encephalomyelitis, rigidity, and myoclonus: a novel glycine receptor antibody. Neurology 2008; 71:1291–2. 34. 20. Deymeer F, Akca S, Kocaman G, et al. Fasciculations, autonomic symptoms and limbic encephalitis: a thymoma-associated Morvan’s-like syndrome. Eur Neurol 2005; 54:235–37. McKeon A, Martinez-Hernandez E, Lancaster E, et al. Glycine receptor autoimmune spectrum with stiff-man syndrome phenotype. JAMA Neurol 2013; 70:44–50. 35. Vincent A, Leite MI, Waters P, Becker C-M, Jacobi C, Meinck H-M. Glycine receptor antibodies in progressive encephalomyelitis with rigidity and myoclonus, hyperekplexia and stiff person syndrome. Ann Neurol 2009; 66:550–51. 36. Boronat A, Gelfand JM, Gresa-Arribas N, et al. Encephalitis and antibodies to dipeptidyl-peptidase-like protein-6, a subunit of Kv4.2 potassium channels. Ann Neurol 2013; 73:120–128. 37. Balint B, Jarius S, Nagel S, et al. Progressive encephalomyelitis with rigidity and myoclonus: A new variant with DPPX antibodies. Neurology 2014; 82:1521–1528. 38. Sabater L, Gaig C, Gelpi E, et al. A novel non-rapid-eye movement and rapideye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5: a case series, characterisation of the antigen, and post-mortem study. Lancet Neurol 2014; 13:575–586. 39. Lancaster E, Martinez-Hernandez E, Titulaer MJ, et al. Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome. Neurology 2011; 77:1698–1701. Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016; 15:391-404. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the eff ects of antibodies. Lancet Neurol 2008; 7:1091–98. Dalmau J, Tuzun E, Wu HY, et al. Paraneoplastic anti-N-methyl-Daspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 2007; 61:25–36. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis:an observational cohort study. Lancet Neurol 2013; 12:157–65. Bartolini L. How do you treat anti-NMDA receptor encephalitis? Neurol Clin Pract 2016; 6:69-72. Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titers at diagnosis and during follow-up of anti NMDA receptor encephalitis: a retrospective study. Lancet Neurol 2014; 13;167-177. 21. Fleisher J, Richie M, Price R, et al. Acquired neuromyotonia heralding recurrent thymoma in myasthenia gravis. JAMA Neurol 2013; 70:1311–1314. 22. 23. Barber PA, Anderson NE, Vincent A. Morvan’s syndrome associated with voltage-gated K+ channel antibodies. Neurology 2000; 54:771–72. Castillo P, Woodruff B, Caselli R, et al. Steroid-responsive encephalopathy associated with autoimmune thyroiditis. Arch Neurol 2006; 63:197–202. Schmitt Se, Pargeon K, Frechette ES, Hirsch LJ, Dalmau J, Friedman D. Extreme delta brush: a unique EEG pattern in adult with anti NMDA receptor encephalitis. Neurology 2012; 79:1094-100. 24. Veciana M, Becerra JL, Fossas P, Muriana D, Sansa G, Santamarina E, Gaig C, Carreño M, Molins A, Escofet C, Ley M, Vivanco R, Pedro J, Miró J, Falip M. Epilepsy Group of the SCN. EEG extreme delta brush: An ictal pattern in patients with anti-NMDA receptor encephalitis. Epilepsy Behav 2015 Jun 10. 25. Takahashi S, Mitamura R, Itoh Y, Suzuki N, Okuno A. Hashimoto encephalopathy: Etiologic considerations. Pediatr Neurol 1994; 11:328-31. 26. Mocellin R, Walterfang M, Velakoulis D. H a s h i m o t o’s e n c e p h a l o p a t h y : E p i d e m i o l o g y, p a t h o g e n e s i s a n d management. CNS Drugs 2007; 21:799-811. Kothbauer-Margreiter I, Sturzenegger M, Komor J, Baumgar tner R, Hess CW. Encephalopathy associated with Hashimoto thyroiditis: Diagnosis and treatment. J Neurol 1996; 243:585-93.
