Lorenzo De Santi

Brain-derived neurotrophic factor and TrkB receptor in experimental autoimmune encephalomyelitis and multiple sclerosis

The interaction between the immune and nervous systems can be both detrimental and beneficial. Experimental autoimmune encephalomyelitis (EAE) is an animal model of autoimmune demyelination that histologically and clinically mimics multiple sclerosis (MS). Myelin-reactive T cells produce and release brain-derived neurotrophic factor (BDNF) directly in the central nervous system, which stimulates tissue repair after traumatic injury. In EAE and MS, T cells in the vicinity of actively demyelinating lesions express BDNF, suggesting a neuroinflammatory reaction that is designed to limit brain damage and contribute to the repair process. Despite some evidence supporting MS therapies that enhance BDNF production by immune cells, no published reports have actually demonstrated that increased BDNF production can substantially ameliorate the clinical symptoms of MS. BDNF binds to a small subset of peripheral T cells that express TrkB, which is the BDNF receptor. This binding confers a partial resistance to apoptosis upon T cell activation, which could underlie the chronic nature of the inflammatory process. Here we will review the main aspects of BDNF and TrkB receptor involvement in neuroprotective autoimmunity in both EAE and MS. We will also discuss the latest findings with respect to the role of the BDNF/TrkB axis in regulating the survival of autoreactive T cells, with a focus on potential selectively immunomodulating strategies that may favor neuroprotection in MS.

Lennox—Gastaut syndrome in adulthood: Clinical and EEG features

PURPOSE We performed a retrospective study to investigate seizure, EEG, social and cognitive outcome in adult LGS subjects. METHODS We retrospectively evaluated 27 LGS patients aged 40-59 years. We assessed in particular the evolution of different seizure types and EEG findings, as well as cognitive and social outcome. RESULTS During the early stages of the disease, all patients presented tonic seizures (TS) during wakefulness and sleep, 20/27 had atypical absences (AA), more rarely other seizure types. EEG showed slow background activity in 21/27 patients, diffuse slow spike-wave discharges (DSSW) during wakefulness in 22/27, and bursts of diffuse fast rhythms (DFR) in sleep in all patients. At last observation, 11 patients only had TS during wakefulness, but all still presented TS during sleep; AA persisted in 6 patients. EEG showed normal BA in 12/27 patients; only 7/27 still presented DSSW. On the contrary, sleep EEG showed the persistence of DFR in all. A moderate to severe cognitive impairment was observed in 26/27 patients. CONCLUSIONS In adult LGS patients TS during sleep remain the major seizure type; moreover, a standard waking EEG may be normal. Thus, polysomnography represents the most important mean of investigation also in adult LGS patients.

Absence of cerebrospinal fluid oligoclonal bands is associated with delayed disability progression in relapsing-remitting MS patients treated with interferon-β

To assess the role of CSF oligoclonal bands (OB) in determining the clinical outcome in patients with relapsing-remitting multiple sclerosis (RRMS) treated with IFN-beta, we carried out a retrospective, multicentre, observational study recruiting 209 RRMS patients from six MS centres from northern, central and southern areas of Italy under treatment with IFN-beta-1a i.m., IFN-beta-1a s.c. and IFN-beta-1b s.c. Twenty-two of 209 patients (10.6%) showed no OB in CSF. The patients without had, at disease onset, significantly higher frequency of visual disturbances (p=0.02) and less sensory involvement (p=0.04) than those with OB. A statistical trend (p=0.056) towards a longer time to reach sustained disability progression during treatment was found in patients without compared to those with OB. Thirty-six of 187 (19%) patients with OB worsened by at least 1 EDSS point compared to none of 22 (0%) OB-negative patients (p=0.017). The delaying of disability progression in OB-negative patients during treatment was significantly dependent only on the number of baseline MRI T2-weighted lesions (p=0.012) that was found to be significantly lower in OB-negative than in OB-positive patients (p=0.04). The absence of OB and low number of baseline T2-weighted lesions in this cohort of MS patients are favourable prognostic factors influencing the clinical response to IFN-beta treatment in RRMS patients.

Higher expression of BDNF receptor gp145trkB is associated with lower apoptosis intensity in T cell lines in multiple sclerosis

Conflicting data exist on expression of gp145trkB, the high affinity receptor for brain-derived neurotrophic factor (BDNF), on peripheral blood immunocompetent cells in multiple sclerosis (MS). We analyzed expression of gp145trkB by western blotting and flow cytometry in myelin basic protein (MBP)- and ovalbumin (OVA)-T cell lines prepared from 12 patients with relapsing-remitting MS and 12 normal healthy subjects (NHS) and correlated it with activation-induced apoptosis. We found a higher percentage of gp145trkB-expressing MBP-T cells in MS patients than in NHS (p=0.011). gp145trkB was mainly expressed by CD8(+) T cells to a higher extent in MS patients than in NHS (p=0.04). MBP-T cell lines from MS patients showed significantly lower apoptosis intensity than those from NHS (p=0.011). We found also a significant negative correlation between gp145trkB expression and apoptosis intensity in MS patients only (p=0.02). OVA-T cell lines showed a gp145trkB expression similar to that of MBP-T cell lines, with a higher expression in MS patients than NHS, and similar correlations with apoptosis intensity in MS. These findings suggest that gp145trkB is mainly expressed on T cell lines from MS patients and that the BDNF/gp145trkB axis is involved in the regulation of peripheral T cell apoptosis in MS.

Clinical-Radiologic Heterogeneity of Occipital Neuralgiform Pain as Multiple Sclerosis Relapse

Occipital neuralgia may be related to traumatic, compressive, or inflammatory injury to the occipital nerve or C2 radicular level and cervical spinal cord lesions. We report a series of 3 patients with definite relapsing‐remitting multiple sclerosis (MS) who experienced sudden occipital neuralgiform pain with or without diminished sensation in the cervical region and associated with magnetic resonance imaging (MRI) evidence of a new active or new T2‐weighted demyelinating C2 cervical lesion. We suggest that sudden paroxysmal occipital pain may signal relapse of MS and cervical MRI with gadolinium should be considered; these patients show good clinical response to high‐dose intravenous corticosteroids.

Impairment of Vertical Saccades From an Acute Pontine Lesion in Multiple Sclerosis

A 62-year-old woman with relapsing-remitting multiple sclerosis suddenly complained of diplopia associated with bilateral adduction impairment, nystagmus of the abducting eye bilaterally, and sparing of abduction, convergence, and vertical eye movements, consistent with bilateral internuclear ophthalmoplegia. Within 1 week, she had developed a complete horizontal gaze paralysis even with the oculocephalic maneuver. Vertical saccades were slow and convergence was preserved. There was a right lower motor neuron seventh cranial nerve palsy. Brain MRI showed a new enhancing lesion involving the pontine tegmentum. Clinical and MRI follow-up showed recovery after 6 months. The slowing of vertical saccades may have been due to spread of the demyelinating lesion to the adjacent paramedian pontine reticular formation, which contains omnipause neurons lying in the raphe interpositus nucleus thought to inhibit excitatory burst neurons for horizontal and vertical saccades. Our patient verifies the fact that vertical saccadic abnormalities may occur from a lesion apparently confined to the pons.

Successful response of non-recovering Ramsay Hunt syndrome to intravenous high dose methylprednisolone

Ramsay Hunt syndrome (RHS) is a frequent cause of facial palsy. It is a consequence of the infection of geniculate ganglion by herpes zoster or herpes simplex virus. In the lack of randomized controlled trials, RHS is empirically treated by a combination therapy of antiviral agents and steroids given orally. However, RHS has, per se, a poorer prognosis than idiopathic facial palsy (Bells palsy). We describe a case series of two patients with RHS unsuccessfully treated with antiviral drugs and oral corticosteroids, showing an almost complete recovery after late administration of intravenous (i.v.) high dose methylprednisolone. Both patients had all recognized negative prognostic factors including age of onset, a high grade facial weakness, absence of R1 and R2 response at blink reflex test, and in the first case, the involvement of greater superficial petrosal nerve. We propose that i.v. high dose methylprednisolone should be considered, even as a late treatment option, in patients with RHS non recovering after standard antiviral and oral steroid therapy as well as presenting clinical features suggestive of a poor prognosis.

Nimodipine confers clinical improvement in two models of experimental autoimmune encephalomyelitis

Multiple sclerosis is characterised by inflammatory neurodegeneration, with axonal injury and neuronal cell death occurring in parallel to demyelination. Regarding the molecular mechanisms responsible for demyelination and axonopathy, energy failure, aberrant expression of ion channels and excitotoxicity have been suggested to lead to Ca2+ overload and subsequent activation of calcium‐dependent damage pathways. Thus, the inhibition of Ca2+ influx by pharmacological modulation of Ca2+ channels may represent a novel neuroprotective strategy in the treatment of secondary axonopathy. We therefore investigated the effects of the L‐type voltage‐gated calcium channel blocker nimodipine in two different models of mouse experimental autoimmune encephalomyelitis (EAE), an established experimental paradigm for multiple sclerosis. We show that preventive application of nimodipine (10 mg/kg per day) starting on the day of induction had ameliorating effects on EAE in SJL/J mice immunised with encephalitic myelin peptide PLP139–151, specifically in late‐stage disease. Furthermore, supporting these data, administration of nimodipine to MOG35–55‐immunised C57BL/6 mice starting at the peak of pre‐established disease, also led to a significant decrease in disease score, indicating a protective effect on secondary CNS damage. Histological analysis confirmed that nimodipine attenuated demyelination, axonal loss and pathological axonal β‐amyloid precursor protein accumulation in the cerebellum and spinal cord in the chronic phase of disease. Of note, we observed no effects of nimodipine on the peripheral immune response in EAE mice with regard to distribution, antigen‐specific proliferation or activation patterns of lymphocytes. Taken together, our data suggest a CNS‐specific effect of L‐type voltage‐gated calcium channel blockade to inflammation‐induced neurodegeneration.

Corrigendum to “Lennox–Gastaut syndrome in adulthood: Clinical and EEG features” [Epilepsy Res. 89 (2–3) (2010) 271–277]

a IRCCS Centro Neurolesi ‘‘Bonino-Pulejo’’, Via Palermo, SS 113, C.da Casazza, 98124 Messina, Italy b Danish Epilepsy Centre, Dianalund, Denmark c Centre Saint-Paul, Hopital Henri Gastaut, Marseille, France d Division of Child Neurology and Psychiatry, Policlinco A. Gemelli, Rome, Italy e Division of Child Neurology and Psychiatry, University of Messina, Messina, Italy Available online 1 June 2010