Autoimmune encephalitis

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There are multiple possible autoimmune encephalitic presentations but perhaps the most important is what is now known as limbic encephalitis. Autoimmune epilepsy due to say GluR3 autoantibodies may be effectively a subtype as permanent neuronal damage can occur.

Contents

Overlap with Guillain-Barré syndrome

Bickerstaff's brainstem encephalitis

Autoimmune neurological syndrome of acute ophthalmoplegia and ataxia.

Patients typically have an antecedent illness, drowsiness, extensor plantar responses or hemisensory loss. Diagnostic criteria have been proposed of[1]:

  1. Progressive, relatively symmetrical external ophthalmoplegia and ataxia by 4 weeks after symptom onset
  2. Disturbance of consciousness or hyperreflexia

It has been associated with IgM antibodies to GM1b and GalNAc-GD1a after Campylobacter jejuni gastroenteritis or mycoplasma pneumoniae and has a relationship to Guillain-Barré syndrome[2].

Miller-Fisher syndrome

Miller-Fisher syndrome (MFS) was first described in 1956 by a Canadian stroke neurologist, Charles Miller-Fisher [3] (who is also recognised as providing the first description of transient ischaemic attacks). The disease is a variant of Guillain-Barre syndrome, found in about 5% of presentations and is currently the subject of much research, as it is a good model for immune mediated injury in the nervous system.

Aetiology

Patients often have a preceding insult to their immune system, and this could be as diverse as vaccination, respiratory tract infection, herpes or mycoplasma infection. It has been noted in particular that many patients will have a preceding infection with Campylobacter jejuni [4], and this offers interesting insights into disease pathogenesis . It is thought that a number of antigenic epitopes exist on the surface of Campylobacter that are structurally similar to certain complex gangliosides. Through a process of molecular mimicry, antibodies raised to Campylobacter also bind to gangliosides found in the body, and produce injury. While a wide range of anti-ganglioside antibodies have been described such as GM1b, GD1a, GD1b, GD1c, GalNAc-GM1b, GT1a and ganglioside complexes (GT1a/GM1 and GQ1b/GM1), it is anti-GQ1b antibodies that are most specific for the syndrome. [5]

Clinical

The classic clinical triad of: ataxia, areflexia, and ophthalmoplegia are present. Bulbar palsy may often be a feature, necessitating referral to ITU. Other variants of GBS ( Ataxic Guillain-Barre Syndrome and Acute Ophthalmoparesis [6] [7]) share many of the features of Miller-Fisher Syndrome, and these conditions are thought to represent a spectrum of MFS

Investigations

CT scan will be normal. LP may show an acellular fluid with elevated protein. EMG may not be diagnostic, but could show evidence of demyelination or conduction block. Anti-ganglioside antibodies, particularly to GQ1b will be positive in 90% of cases [8]. Cases negative for anti-GQ1b antibodies may be due to anti-GAD antibodies[5].

Treatment

Intravenous immunoglobulin therapy and plasmapharesis are used.[9] Main restrictions at the moment are cost and accessibility.

A recent Cochrane review did not show any evidence that steroids alone produce an improvement in symptoms, and indeed their use was associated with a slight (statistically insignificant) increase in steroid related complications including diabetes and hypertension.[10] However, one study did suggest that the time to independent walking is improved if intravenous steroid is given in conjunction with immunoglobulin, and it can therefore be used as an adjunct treatment in cases where the patient’s recovery is prolonged.[11]

Anti-Ma2 autoimmune encephalitis

This seems to have a more varied presentation than many other autoimmune encephalitis, which may be because of multiple autoantigens in some cases, even though anti-Ma2 is predominant. About a quarter to a third have one or more of[12]:

Rarely:

  • Atypical parkinsonism
  • Hypokinetic syndrome with a tendency to eye closure and dramatic reduction of verbal output.

Association testicular germ-cell tumours. Additional antibodies to Ma1 associated with tumours other than testicular cancer and ataxia.

Response to immunosuppression is unpredictable but can be good. In males a vigorous approach in patients with only anti-Ma2 antibodies seems justified. It has been suggested that orchiectomy is justified if[13]:

  1. Anti-Ma2 antibodies in association with MRI or clinical features compatible with Ma2-encephalitis
  2. Life-threatening or progressive neurological deficits
  3. Age < 50 years
  4. Absence of other tumors
  5. New testicular enlargement or cyptorchidism or ultrasound evidence of testicular microcalcifications

Anti-CV2/CRMP-5 autoimmune encephalitis

Limbic encephalitis

First described as recently as 1968 as a paraneoplastic phenomena it is increasingly being recognised and successfully treated with some idiopathic forms being quite responsive to immunosuppression. It presents with:

  • Rapidly progressive short-term memory deficits
  • Psychiatric symptoms
  • Epilepsy

As of 2008 about 40% of the autoantigens responsible remain unidentified.

Anti-VGKC limbic encephalitis

The recognition that immunosuppressive treatment of limbic encephalitis associated with antibodies to voltage gated potassium channels (VGKC) revolutionised the field and indeed by encouraging appropriate CSF and serum characterisation transformed a rare condition to one that was quite common but obviously previously unsuspected. Typically rapidly progressive:

Treatment is with steroids, plasma exchange and intravenous immunoglobulin.

Anti-Hu limbic encephalitis

  • Rapidly evolving impairment in consciousness
  • EEG evidence of lateralized pseudoperiodic sharp-wave discharges
  • Ataxia
  • Sensory neuropathy

Anti-Ma2 limbic encephalitis

Is only about 25% of Anti-Ma2 autoimmune encephalitis

Anti-CV2/CRMP-5 limbic encephalitis

Has been reported with tumour associations.

Anti-NMDAR limbic encephalitis

Due to antibodies to the NR1 and NR2 hetromers of the NMRA receptor [14] presents with:

There is an association with teratomas such as ovarian dermoid cysts which is important as resection of the tumour is potentially curative[15]. However these antibodies have been detected in 30% of SLE patients, with or without neuropsychiatric impairments. NR2 autoantibodies are also found in patients with epilepsy (33%), non-specific encephalitis and stroke[16]. The CSF 14-3-3 protein can be raised so is not helpful in differential diagnosis excluding CJD.

Stiff person syndrome

Stiff person syndrome (stiff-person syndrome, stiff-man syndrome, SPS) should be suspected with:

  • Progressive muscle rigidity
  • Superimposed painful muscle spasms
  • Gait impairment due to continuous motor activity

It is a neurological disease associated with the development of autoantibodies, usually to glutamic acid decarboxylase but also to the synaptic membrane protein amphiphysin[17]. The rare progressive encephalomyelitis with rigidity and myoclonus (PERM, stiff person syndrome plus) is associated with glycine receptor antibodies. The presence of anti-GAD65 antibodies are specific[18] but as a number of other conditions can cause similar clinical presentations the literature is confusing. The paraneoplastic presentation may be different to the non-paraneoplastic condition. Profolol has possible benefit[19]. Patients are more likely to have the condition with:

  • Rigidity and painful spasms of the lumbar paraspinal, abdominal, and occasionally proximal leg muscles
  • Associated lumbar hyperlordosis
  • Intrathecal synthesis (IS) of GAD-ab

Involvement of the upper limbs and distal lower limbs is rarer. However the condition appears to be under diagnosed.

There are associations with type 1 diabetes, Other conditions associated with GAD antibodies include[20]:

PERM

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is caused by autoantibodies to the glycine receptor (GlyR)[24]. There is an encephalomyelitis with:

  • Myoclonus
  • Rigidity
  • Brainstem signs including autonomic dysfunction
  • Some times cerebellar ataxia
  • Some times isolated temporal lobe epilepsy

The neuropathology includes brainstem perivascular cuffing and neuronal loss.

It is part of the spectrum of stiff person syndrome (SPS). It has been associated with thymoma[25].

Treatment

Autoimmune epilepsy

Antibodies to say glutamate/AMPA subtype 3 (anti-GluR3B) are found in up to 30% of patients with epilepsy but are close to universal in some refractory epilepsy such as that found in Rasumussen's syndrome[26]. It is difficult to sort out chicken and egg, but animal models suggest such antibodies are neurotoxic. Indeed there are increasing numbers of case reports of successful immunosuppressive therapy as in anti-GAD antibody-positive refractory status epilepticus[27].

Rasmussen's encephalitis

Usually childhood onset with unclear aetiology with[28]:

  • Focal seizures with predominant motor component
  • Often epilepsia partialis continua
  • Progressive neurological deterioration
    • Unilateral hemispheric atrophy
      • Focal white matter hyperintensity and insular cortical atrophy on neuroimaging
      • Progressive unilateral motor defect
    • Slow EEG activity over the entire contralateral hemisphere, with
    • Inflammatory histopathology.

There is an association with anti-GluR3 antibodies but this may be secondary. Munc18-1 antibodies have also been found in 20% of cases[29].


Surgical exclusion of the affected hemisphere is the only treatment, but this is only an option in young children. Later onset patients also tend to have more occipital involvement.

References

  1. Odaka M, Yuki N, Yamada M, Koga M, Takemi T, Hirata K, Kuwabara S. Bickerstaff's brainstem encephalitis: clinical features of 62 cases and a subgroup associated with Guillain-Barré syndrome. Brain : a journal of neurology. 2003 Oct; 126(Pt 10):2279-90.(Link to article – subscription may be required.)
  2. Odaka M, Yuki N, Yamada M, Koga M, Takemi T, Hirata K, Kuwabara S. Bickerstaff's brainstem encephalitis: clinical features of 62 cases and a subgroup associated with Guillain-Barré syndrome. Brain : a journal of neurology. 2003 Oct; 126(Pt 10):2279-90.(Link to article – subscription may be required.)
  3. Fisher, M An unusual variant of acute idiopathic polyneuritis (syndrome of ophthalmoplegia, ataxia and areflexia). 1956 Jul 12;255(2):57-65.
  4. Endtz,H.P., Ang,C.W., Van den,B.N., Duim,B., Rigter,A., Price,L.J., Woodward,D.L., Rodgers,F.G., Johnson,W.M., Wagenaar,J.A. et al. 2000. Molecular characterization of Campylobacter jejuni from patients with Guillain-Barre and Miller Fisher syndromes. J.Clin.Microbiol. 38:2297-2301
  5. a b Dagklis IE, Papagiannopoulos S, Theodoridou V, Kazis D, Argyropoulou O, Bostantjopoulou S. Miller-Fisher Syndrome: Are Anti-GAD Antibodies Implicated in Its Pathophysiology? Case reports in neurological medicine. 2016; 2016:3431849.(Link to article – subscription may be required.)
  6. Willison HJ, Yuki N. Peripheral neuropathies and anti-glycolipid antibodies 2002 Dec;125(Pt 12):2591-625.
  7. Odaka,M., Yuki,N., and Hirata,K. Anti-GQ1b IgG antibody syndrome: clinical and immunological range. 2001 Jan;70(1):50-5
  8. Chiba,A., Kusunoki,S., Obata,H., Machinami,R., and Kanazawa,I. Serum anti-GQ1b IgG antibody is associated with ophthalmoplegia in Miller Fisher syndrome and Guillain-Barre syndrome: clinical and immunohistochemical studies Peripheral neuropathies and anti-glycolipid antibodies 1993 Oct;43(10):1911-7
  9. Shahar,E.Current therapeutic options in severe Guillain-Barre syndrome. 2006 Jan-Feb;29(1):45-51.
  10. Hughes RA, Swan AV, van Koningsveld R, van Doorn PA. Corticosteroids for Guillain-Barre syndrome. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD001446. Review.
  11. The Dutch Guillain-Barre Study Group. Treatment of Guillain-Barre syndrome with high-dose immune globulins combined with methylprednisolone: a pilot study. Ann Neurol. 1994 Jun;35(6):749-52. Erratum in: Ann Neurol 1994 Sep;36(3):457.
  12. Dalmau J, Graus F, Villarejo A, Posner JB, Blumenthal D, Thiessen B, Saiz A, Meneses P, Rosenfeld MR. Clinical analysis of anti-Ma2-associated encephalitis. Brain : a journal of neurology. 2004 Aug; 127(Pt 8):1831-44.(Link to article – subscription may be required.)
  13. Mathew RM, Vandenberghe R, Garcia-Merino A, Yamamoto T, Landolfi JC, Rosenfeld MR, Rossi JE, Thiessen B, Dropcho EJ, Dalmau J. Orchiectomy for suspected microscopic tumor in patients with anti-Ma2-associated encephalitis. Neurology. 2007 Mar 20; 68(12):900-5.(Link to article – subscription may be required.)
  14. Wilder-Smith EP, Ng ES. The writing on the wall. Lancet 2008;372:344
  15. Sabin TD, Jednacz JA, Staats PN. Case records of the Massachusetts General Hospital. Case 26-2008. A 26-year-old woman with headache and behavioral changes. The New England journal of medicine. 2008 Aug 21; 359(8):842-53.(Link to article – subscription may be required.)
  16. Levite M, Ganor Y. Autoantibodies to glutamate receptors can damage the brain in epilepsy, systemic lupus erythematosus and encephalitis. Expert review of neurotherapeutics. 2008 Jul; 8(7):1141-60.(Link to article – subscription may be required.)
  17. Espay AJ, Chen R. Rigidity and spasms from autoimmune encephalomyelopathies: stiff-person syndrome. Muscle & nerve. 2006 Dec; 34(6):677-90.(Link to article – subscription may be required.)
  18. Burbelo PD, Groot S, Dalakas MC, Iadarola MJ. High definition profiling of autoantibodies to glutamic acid decarboxylases GAD65/GAD67 in stiff-person syndrome. Biochemical and biophysical research communications. 2008 Feb 1; 366(1):1-7.(Link to article – subscription may be required.)
  19. Hattan E, Angle MR, Chalk C. Unexpected benefit of propofol in stiff-person syndrome. Neurology. 2008 Apr 29; 70(18):1641-2.(Link to article – subscription may be required.)
  20. Saiz A, Blanco Y, Sabater L, González F, Bataller L, Casamitjana R, Ramió-Torrentà L, Graus F. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain : a journal of neurology. 2008 Aug 7.(Epub ahead of print) (Link to article – subscription may be required.)
  21. Folli F, Solimena M, Cofiell R, Austoni M, Tallini G, Fassetta G, Bates D, Cartlidge N, Bottazzo GF, Piccolo G. Autoantibodies to a 128-kd synaptic protein in three women with the stiff-man syndrome and breast cancer. The New England journal of medicine. 1993 Feb 25; 328(8):546-51.(Link to article – subscription may be required.)
  22. De Camilli P, Thomas A, Cofiell R, Folli F, Lichte B, Piccolo G, Meinck HM, Austoni M, Fassetta G, Bottazzo G. The synaptic vesicle-associated protein amphiphysin is the 128-kD autoantigen of Stiff-Man syndrome with breast cancer. The Journal of experimental medicine. 1993 Dec 1; 178(6):2219-23.
  23. Floyd S, Butler MH, Cremona O, David C, Freyberg Z, Zhang X, Solimena M, Tokunaga A, Ishizu H, Tsutsui K, De Camilli P. Expression of amphiphysin I, an autoantigen of paraneoplastic neurological syndromes, in breast cancer. Molecular medicine (Cambridge, Mass.). 1998 Jan; 4(1):29-39.
  24. Turner MR, Irani SR, Leite MI, Nithi K, Vincent A, Ansorge O. Progressive encephalomyelitis with rigidity and myoclonus: glycine and NMDA receptor antibodies. Neurology. 2011 Aug 2; 77(5):439-43.(Link to article – subscription may be required.)
  25. Uehara T, Murai H, Yamasaki R, Kikuchi H, Shigeto H, Ohyagi Y, Kira J. Thymoma-associated progressive encephalomyelitis with rigidity and myoclonus successfully treated with thymectomy and intravenous immunoglobulin. European neurology. 2011; 66(6):328-30.(Link to article – subscription may be required.)
  26. Ganor Y, Goldberg-Stern H, Amrom D, Lerman-Sagie T, Teichberg VI, Pelled D, Futerman AH, Zeev BB, Freilinger M, Verheulpen D, Van Bogaert P, Levite M. Autoimmune epilepsy: some epilepsy patients harbor autoantibodies to glutamate receptors and dsDNA on both sides of the blood-brain barrier, which may kill neurons and decrease in brain fluids after hemispherotomy. Clinical & developmental immunology. 2004 Sep-Dec; 11(3-4):241-52.
  27. Kanter IC, Huttner HB, Staykov D, Biermann T, Struffert T, Kerling F, Hilz MJ, Schellinger PD, Schwab S, Bardutzky J. Cyclophosphamide for anti-GAD antibody-positive refractory status epilepticus. Epilepsia. 2008 May; 49(5):914-20.(Link to article – subscription may be required.)
  28. Granata T, Gobbi G, Spreafico R, Vigevano F, Capovilla G, Ragona F, Freri E, Chiapparini L, Bernasconi P, Giordano L, Bertani G, Casazza M, Dalla Bernardina B, Fusco L. Rasmussen's encephalitis: early characteristics allow diagnosis. Neurology. 2003 Feb 11; 60(3):422-5.
  29. Alvarez-Barón E, Bien CG, Schramm J, Elger CE, Becker AJ, Schoch S. Autoantibodies to Munc18, cerebral plasma cells and B-lymphocytes in Rasmussen encephalitis. Epilepsy research. 2008 Jul; 80(1):93-7.(Link to article – subscription may be required.)
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