Faculty Bibliography

OBJECTIVE:The clinical and electrographic features of seizures in anti-LGI1 encephalitis are distinct from those seen in other autoimmune encephalitides or non-encephalitic epilepsies. One electroclinical phenomenon specific to the condition consists of lateralized motor spasms, known as faciobrachial dystonic seizures (FBDS). An electrodecremental pattern overriding a "DC shift" has been described as the EEG correlate of these spasms. We sought to further characterize this pre-spasm infraslow activity (ISA). METHODS:Continuous video-EEG recordings were acquired in four patients with anti-LGI1 encephalitis: each had frequent motor spasms/FBDS as well as frequent subclinical temporal lobe seizures (an independent indicator of anti-LGI1 encephalitis). RESULTS:In artifact-free recordings obtained using clinical amplifiers equipped with a low frequency analog filter of 0.07 Hz, ISA reliably preceded clinical onset of the motor spasms by ∼1.2 s and preceded the electrodecremental pattern by ∼700 ms. Pre-spasm ISA was invariably recorded contralateral to FBDS, with a voltage topographic maximum over the mid frontal region. The pre-movement ISA differed from the Bereitschaftspotential in timing and topography and was an order of magnitude higher in amplitude. Sporadic FBDS that occurred in association with temporal lobe seizures were preceded by identical ISA. CONCLUSIONS:The motor spasms of anti-LGI1 encephalitis are preceded by frontal ISA. A paucity of data at the microscale level precludes mechanistic explanations at the macroscale level, or even determination of the relative contributions of neurons and glia in the generation of the ISA. SIGNIFICANCE/CONCLUSIONS:Although fundamental cellular mechanisms await elucidation, the pre-spasm ISA represents a singular and readily identifiable EEG response to this autoimmune brain disorder.

In a cohort of 34 patients with autoimmune limbic encephalitis and/or epilepsy, we identified 4 patients exhibiting claustrum fluid-attenuated inversion recovery (FLAIR) hyperintensities. All 4 patients presented with explosive onset of seizures and developed medically intractable epilepsy, and 2 exhibited a marked response to immunotherapy. Associated features included cognitive and behavioral disturbances (4/4), cerebrospinal fluid (CSF) lymphocytic pleocytosis (3/4), and a neural autoantibody (2/4). Electroencephalogram (EEG) features consisted of slow wave activity and epileptiform discharges in frontal and parasagittal regions, where ictal patterns were captured in 1 patient. In 1 patient, magnetoencephalographic source imaging of interictal spikes revealed dipole sources in anterior insular or subinsular localizations, mirroring claustrum FLAIR hyperintensities, which developed after a short lag from presentation and resolved in all but 1 patient. These MRI abnormalities were isolated (2/4) or associated with mesial temporal hyperintensities (2/4). Claustrum FLAIR hyperintensities may be a useful MRI marker of autoimmune epilepsy.

Leucine-rich glioma inactived-1 (LGI1) antibodies are associated with limbic encephalitis and distinctive seizure types, which are typically immunotherapy-responsive. Although nonspecific electroencephalography (EEG) abnormalities are commonly seen, specific EEG characteristics are not currently understood to be useful for suspecting the clinical diagnosis. Based on initial observations in two patients, we analyzed the clinical features and EEG recordings in a larger series of patients (n = 9) and describe a novel ictal pattern that can suggest the diagnosis of LGI1-antibody-mediated encephalitis, even in the absence of typical clinical features. As expected, psychiatric and cognitive symptoms were common, as were tonic seizures associated with EEG electrodecremental events (often with the so-called faciobrachial dystonic semiology). Remarkably, in five patients, a near absence of interictal epileptiform discharges contrasted with frequent subclinical temporal lobe seizures, at times triggered by hyperventilation. This latter EEG pattern may facilitate early diagnosis of this serious but potentially treatable condition.

BACKGROUND:Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome can present management challenges. Refractory seizures and stroke-like episodes leading to disability are common. PATIENT/METHODS:We analyzed the clinical, electrophysiologic, and radiologic data of a 22-year-old woman with multiple episodes of generalized and focal status epilepticus and migratory cortical stroke-like lesions who underwent muscle biopsy for mitochondrial genome sequencing. RESULTS:Although initial mitochondrial genetic testing was negative, muscle biopsy demonstrated a mitochondrial DNA disease-causing mutation (m.3260A > G). New antiepileptic medications were added with each episode of focal status epilepticus with only temporary improvement, until a modified ketogenic diet and magnesium were introduced, leading to seizure freedom despite development of a new stroke-like lesion, and subsequent decrease in frequency of stroke-like episodes. We propose a metabolic model in which the ketogenic diet may lead to improvement of the function of respiratory chain complexes. CONCLUSIONS:The ketogenic diet may lead to improvement of mitochondrial dysfunction in MELAS, which in turn may promote better seizure control and less frequent stroke-like episodes.

The homeodomain transcription factor Pitx3 is critical for the survival of midbrain dopaminergic (mDA) neurons. Pitx3-deficient mice exhibit severe but selective developmental loss of mDA neurons, with accompanying locomotor deficits resembling those seen in Parkinson's disease (PD) models. Here, we identify specific mDA cell subpopulations that are consistently spared in adult Pitx3-hypomorphic (aphakia) mice, demonstrating that Pitx3 is not indiscriminately required by all mDA neurons for their survival. In aphakia mice, virtually all surviving mDA neurons in the substantia nigra (SN) and the majority of neurons in the adjacent ventral tegmental area (VTA) also express calbindin-D28k, a calcium-binding protein previously associated with resistance to injury in PD and in animal models. Cell-mapping studies in wild-type mice revealed that Pitx3 is primarily expressed in the ventral SN, a region particularly susceptible to MPTP and other dopaminergic neurotoxins. Furthermore, Pitx3-expressing SN cells are preferentially lost following MPTP treatment. Finally, SN mDA neurons in Pitx3 hemizygous mice show increased sensitivity when exposed to MPTP. Thus, SN mDA neurons are represented by at least two distinct subpopulations including MPTP-resistant Pitx3-autonomous, calbindin-positive neurons, and calbindin-negative Pitx-3-dependent cells that display elevated vulnerability to toxic injury, and probably correspond to the subpopulation that degenerates in PD. Impairment of Pitx3-dependent pathways therefore increases vulnerability of mDA neurons to toxic injury. Together, these data suggest a novel link between Pitx3 function and the selective pattern of mDA cell loss observed in PD.