Introduction:

The manifestations due to anti Gad65 antibodies are variable: insulin-dependent diabetes, poly endocrine pathology, neurological manifestations (Stiff-Person syndrome, opso-myoclonus ...) [6, 7, 12, 14, 16]. Encephalitis associated with the glutamic acid decarboxylase (GAD) antibody causes seizures of the temporal lobe [4].

There is an inhibition of GAD function, this would lower the seizure threshold which can contribute to the development of drug-resistant epilepsy [8].

For the picture of associated limbic encephalitis, epilepsy is often refractory, temporal in type, and may be the main sign or the only clinical presentation [11]. There are two scenarios, either acute or subacute convulsive seizures, or a state of refractory epilepticus, accompanied by varying degrees of cognitive and psychiatric disorders, producing the picture of limbic encephalitis [8, 9], or chronic epilepsy without clinical evidence or MRI of active inflammation [5]. Anti GAD65 are of very little paraneoplastic origin, especially if the main presentation is epilepsy [3,17].

The usual additional examinations do little to aid diagnosis. The electroencephalograph can show ictal or inter ictal discharges, most often temporal, and a non-specific temporal slowdown (see figure.3) The cerebral MRI is often abnormal, showing a hyper signal in T2 / Flair, and a “Swelling” in the unilateral or bilateral mesial temporal structures (see figure 1 and 2) [2,10].

In the cytochemical study of the CSF, one can find a hyper proteinorachy, and especially oligo-clonal bands in the CSF.

The assay of the antibody makes it possible to confirm the diagnosis, which must be made in the CSF, in the event of neurological manifestations, requiring high rates (ranging from 2,000 to 5,000,000 IU / ml) [1], whereas in type 1 autoimmune diabetes, they are present at low levels (<2000 IU) [1].

Epilepsy is difficult to treat because it is often refractory, hence the need for early, more aggressive and chronic immunosuppressive or immunomodulatory therapy. First-line treatment is first initiated (Methylprednisolone IV, with a possible oral relay, Immunoglobulin IV, and plasma exchanges) [13,15,18], then second-line treatment such as Cyclophosphamide, until clinical improvement, and / or Rituximab.

We report a case to discuss the diagnosis and the therapeutic strategy and to obtain a cure.

Observation:

This 42-year-old patient, with a history of DID on insulin, thyroiditis with hypothyroidism on Levothyrox, and vitiligo, consults for rapid onset memory problems, about 07 months ago, associated with episodes paroxysmal, brief, like a state of anxiety and then nauseating sensations, lasting about one minute, almost daily. The evolution was made towards aggravation with the appearance of paresthesias of the left hemibody, all in an apyretic cotext.

The admission examination did not find any deterioration in the general condition, revealing a vitiligo of the extremities and of the face. The neurological examination did not find any motor deficit, cerebellar ataxia, or mental confusion. Neuropsychological tests have been carried out revealing impairment of memory functions, difficulty in attention and concentration, with a lack of words, very significant anxiety.

The patient then presented, temporal type epileptic seizures (contact breakdowns with oro-alimentary and gestural automatisms preceded by auras of olfactory hallucinations and epigastric ball type, and accompanied by a state of anxiety), several times a day, resistant to anti epileptics (Levetiracetam 3gram / day, Lamotrigine 200mg / day).

Brain MRI revealed a hyper signal in T2 and FLAIR, hippocampi (uncus temproal, hippocampal gyrus and para hippocampus) with contrast enhancement. A Video-EEG highlighted a recording of bilateral temporal crises, predominantly right, electro-clinical with type of temporo-mesial crisis. Finally, the CSF examination found a hyper proteinorachia at 0.7 g / l without cellularity, presence of anti GAD65 antibodies in a very high titer which was greater than 6750 IU / ML.

Figure.2: Brain MRI (Flair sequence, cross section): bilateral temporo-mesial hyper signal. CHU Tizi-Ouzou, Neurology (H. Si Ahmed).

Figure.3: Brain MRI (Flair sequence, coronal section): hippocampal hyper signal. CHU Tizi-Ouzou. Neurology (H. Si Ahmed).

Figure.1: EEG: moderate, predominantly bi-temporal brain pain, with electro-clinical recording of seizures with right temporal starting point, sometimes on the left. CHU Tizi-Ouzou, Neurology (H. Si Ahmed)

After eliminating the differential diagnoses by additional examinations (anti TPO, serologies, PCR, autoimmunity assessment, intracellular and membrane antibodies ...), the diagnosis of encephalitis with anti GAD65 is retained. At the end of an extensive assessment (tumor markers, TLT, TAP, whole PETscan), the search for a paraneoplastic origin of this encephalitis remained negative.

Once the diagnosis was established, the patient received Methylprednisolone intravenously (one gram / day for 05 days) followed by intravenous Immunoglobulins (0.4 g / kg / day for 05 days), but without any significant clinical improvement, hence the introduction of plasmapheresis (3 sessions) then two cures of Rituximab, with a relay by Cyclophosphamide (6 cures), which led to a spectacular improvement with improvement in cognitive functions and a total disappearance of seizures.

Discussion:

In front of this rapidly evolving clinical picture associating memory disorders of recent events, temporal epilepsy attacks, or even mental disorders (anxiety and irritability, perplexity), we mentioned the diagnosis of limbic encephalitis, confirmed by cerebral MRI . The analysis of the cerebrospinal fluid allowed us to think of an inflammatory origin by the discovery of a hyper proteinorachia and the presence of oligoclonal bands. Given the presence of an autoimmune field (vitiligo, autoimmune thyroiditis, diabetes) and the results of the usual complementary examinations (temporal anomalies with the EEG, temporal hyper signal with cerebral MRI, and presence of inflammation in the LCR), we thought of an autoimmune encephalitis with autoantibodies, after eliminating other etiologies (infectious such as herpes, and other inflammatory etiologies such as Gougerot-sjogren syndrome and Hashimoto encephalopathy , paraneoplastic encephalitis like that of anti Hu.).

The diagnosis of autoimmune encephalitis anti glutamate decarboxylases (GAD65) is thus retained, after the results of the assay in the CSF of the various membrane and intracellular antibodies (NMDA, CAPSR2, GAD .....), which returned in favor a very high titer of anti GAD65 antibodies (greater than 6750 IU / mL).

The association of anti-GAD65 antibodies with refractory epilepsy has been rarely described. Anti-GAD neurological syndromes are rare, described recently, most often in connection with a dysimmune origin and very little paraneoplastic origin. In our patient, a paraneoplastic origin was excluded by an exhaustive assessment.

Epilepsy associated with anti-GAD is difficult to treat with anti-epileptic drugs, because it is often refractory, hence the interest of a more aggressive and chronic immunosuppressive treatment (decrease the autoimmune process and increase GABA ). 1st line treatment (intravenous corticosteroids with oral relay, IV immunoglobulins and plasma exchanges), is effective in certain cases, but may be insufficient, hence the introduction of cyclophosphamide until clinical improvement, and rituximab is effective in the treatment of patients with epilepsy with limbic encephalitis, which can be used as an inducing treatment [13,15,18]. Azathioprine, and mycophenolate mofetil, are used especially in chronic focal epilepsy [13,15,18].

Conclusion:

Focal epilepsy, especially temporal, of unexplained etiology, of recent appearance, should encourage the search for anti GAD Ab, particularly those which are refractory. Early diagnosis of anti-Gad65 antibody encephalitis conditions the ability to control seizures and prevent debilitating cognitive and psychiatric complications by introducing aggressive and early immunosuppressive therapy (Endoxan, Rituximab, mycophenolate mofetil, etc.). The spectrum of anti GAD65 epilepsy is not completely clear. Controlled prospective studies would remain essential.