Ioannis Markakis

Opsoclonus–myoclonus–ataxia syndrome with autoantibodies to glutamic acid decarboxylase

Opsoclonus-myoclonus-ataxia syndrome (OMS) is a rare neurological disorder of probably autoimmune origin. Most cases are associated with a remote neoplasm or a viral infection; however in some instances no underlying aetiology can be demonstrated. We report the presence of anti-glutamic acid decarboxylase antibodies (anti-GAD Abs) in the serum and CSF of a patient with idiopathic OMS. Treatment with intravenous immunoglobulin led to a remarkable clinical improvement with parallel reduction of anti-GAD titers. Anti-GAD Abs have been associated with several neurological syndromes. They could also be responsible for the clinical triad of OMS, by impairing GABAergic transmission in specific brainstem and cerebellar circuits. We propose that testing for anti-GAD Abs should be performed in OMS, especially when no other aetiological association can be demonstrated.

Reduced expression of metabotropic glutamate receptor 2mRNA in T cells of ALS patients.

Metabotropic glutamate receptors alter the vulnerability of neurons to excitotoxic damage and are reported to display abnormal expression in the central nervous system of ALS patients. Using reverse transcriptase polymerase chain reaction, we investigated the mRNA expression of specific metabotropic glutamate receptor subtypes in T lymphocytes of 20 patients with sporadic ALS, compared with healthy age‐matched control subjects and patients with other neurological disorders. The levels of metabotropic glutamate receptor 2 mRNA were markedly reduced, whereas the expression of other subtypes (1b, 3, 8) was similar to control levels. Our findings may provide a reliable peripheral marker of the glutamatergic dysfunction that characterizes ALS. Ann Neurol 2006

Immunotherapy-responsive limbic encephalitis with antibodies to glutamic acid decarboxylase

Glutamic acid decarboxylase (GAD) has been recently identified as a target of humoral autoimmunity in a small subgroup of patients with non-paraneoplastic limbic encephalitis (NPLE). We present a patient with NPLE and positive anti-GAD antibodies who showed significant improvement after long-term immunotherapy. A 48-year old female was admitted with a two-year history of anterograde amnesia and seizures. Brain MRI revealed bilateral lesions of medial temporal lobes. Screening for anti-neuronal antibodies showed high anti-GAD titers in both serum and cerebrospinal fluid (CSF) with strong evidence of intrathecal production. The patient received treatment with prednisolone and long-term plasma exchange. During a 12-month follow-up, she exhibited complete seizure remission and an improvement in memory and visuo-spatial skills. Anti-GAD antibodies may serve as a useful marker to identify a subset of NPLE patients that respond to immunoregulatory treatment.

Aberrant modulation of a delayed rectifier potassium channel by glutamate in Alzheimer's disease

In Alzheimers disease (AD), potassium channel abnormalities have been reported in both neural and peripheral tissues. Herein, using whole-cell patch-clamp, we demonstrate an aberrant glutamate-dependent modulation of K(V)1.3 channels in T lymphocytes of AD patients. Although intrinsic K(V)1.3 properties in patients were similar to healthy individuals, glutamate (1-1000 microM) failed to yield the hyperpolarizing shift normally observed in K(V)1.3 steady-state inactivation (-4.4+/-2.7 mV in AD vs. -14.3+/-2.5 mV in controls, 10 microM glutamate), resulting in a 4-fold increase of resting channel activity. Specific agonist and antagonist data indicate that this abnormality is due to dysfunction of cognate group II mGluRs. Given that glutamate is present in plasma and that both mGluRs and K(V)1.3 channels regulate T-lymphocyte responsiveness, our finding may account for the presence of immune-associated alterations in AD. Furthermore, if this aberration reflects a corresponding one in neural tissue, it could provide a potential target in AD pathogenesis.

Paraneoplastic limbic encephalitis resembling acute herpetic encephalitis.

Introduction. Paraneoplastic limbic encephalitis (PLE) is a rare disorder that typically follows a chronic or subacute course of personality changes, memory loss, seizures, and hallucinations. Early diagnosis is difficult and characteristic symptoms can be mimicked by a variety of conditions. We present a case of PLE, initially presenting as acute herpetic encephalitis. Case Presentation. A 56-year-old male was admitted for evaluation of acute onset headache, fever, and confusion. On neurological examination he was confused with MMSE score of 15/30. CSF analysis revealed marked lymphocytic pleocytosis. A possible diagnosis of acute herpetic encephalitis was rendered and patient was treated with acyclovir. CSF PCR was negative. Cranial MRI revealed bilateral hyperintense lesions in medial temporal lobes with contrast enhancement. Despite treatment with acyclovir patient was deteriorated; thus, a paraneoplastic syndrome was suspected. Chest CT showed a right paratracheal lymph node mass, while a biopsy revealed neuroendocrine lung cancer. Auto antibodies to Hu were also detected. The patient was treated with steroids and chemotherapy. Six months later, he had complete tumour remission and marked neurological improvement. Discussion. PLE can rarely invade acutely, being indistinguishable from herpetic encephalitis. Inclusion of PLE in the differential diagnosis of acute encephalitis is of great clinical significance.

Clinical Heterogeneity of Guillain-Barré Syndrome in the Emergency Department: Impact on Clinical Outcome

Guillain-Barré syndrome (GBS) is mainly classified into acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). Although diagnosis of GBS requires progressive weakness and universal areflexia or hyporeflexia, cases of GBS with preserved or increased deep tendon reflexes (DTRs) have been increasingly recognized. We report three cases of GBS, presenting at a single unit in six months. Our first case presented with pure sensory symptoms. The second case had nonspecific generalized weakness, while the third presented with typical ascending weakness. One of our patients had preserved DTRs, while the other two had increased DTRs. Our two cases with hyperreflexia were found to have a preceding Campylobacter jejuni infection and anti-ganglioside antibodies, and their electrophysiological studies revealed AMAN. The other case had an AIDP. Only one case was offered a diagnosis and treatment from the first emergency department (ED) visit and had a better clinical outcome. Clinical diagnosis of GBS in the ED can be challenging. Delay in diagnosis of GBS in the ED is common due to cases with intact or increased DTRs, atypical pattern of weakness, or pure sensory symptoms. Emergency physicians should be aware of GBS clinical heterogeneity, because early diagnosis and treatment improve clinical outcome.

Interferon beta 1a treatment induces the presence of autoreactive antibodies (ARAB) in patients with relapsing–remitting multiple sclerosis (RRMS)

injury (SCI) in rodent. However, it is still unclear that the PACAP induced by hMSCs contributes to the cellar protection. Therefore, we examined effect of hMSCs on SCI of PACAP gene deficient mice. We also determined that hMSCs partially suppressed neural inflammation through PACAP with host tissues. Under inhalation of anesthesia, mice either PACAP+/+ (wild) or +/− (KO) were subjected to spinal cord transection by a razor at level of Th9–10 intervertebral spinal cord. One day later, the mice were injected hMSCs (5 × 10 cells/0.5 μL) or vehicle one caudal the intervertebral spinal cord. The mice were scored locomotor activity detected by Basso Mouse Scale (BMS) and evaluated injury area with glial fibrillary acidic protein (GFAP) surrounded area at 7 days post operation. We also examined mouse PACAP and PACAP specific receptor (PAC1R) and human or mice proand anti-inflammatory cytokine gene expressions. WTmice implanted hMSCs into spinal cord ameliorated significantly locomotor activity and injury volume to compare with vehicle-treated one. The protections were canceled by inviable hMSCs implanted into WT mice and by viable hMSCs implanted into KO mice. Spinal cord implanted hMSCs expressed an increase of mouse PACAP gene, but not PAC1R. The hMSCs implanted WT animals were decreased mouse IL-1, TNF-alpha, IL-10 and TGF-beta, and increased IL-4 compared with vehicle treatedWT one. However, given hMSCs into KOmice, IL-1, TGFbeta and IL-4 expressed similar to vehicle-treatedWT one. These results suggest that hMSCs suppress neural damage partially mediated by PACAP of mice and decrease of IL-1 and TGF-beta and increase of IL-4 were regulated by the PACAP expression.