PMC

Age-specific appearance of spasms in DLP pups. Daily monitoring with two daily 2h-sessions was done starting at P4 till P20 in DLP pups. Spasms appear at P4, peak during P4–7 and disappear after P13.

Vigabatrin transiently suppresses DLP spasms.
Vigabatrin treatment (20 mg/kg/dose i.p. twice daily (bid), n=6 male pups), starting at P4) significantly reduced the frequency of spasms at P5 only. The results were compared with vehicle-treated male pups (n=9 pups). * P=0.0058 compared to controls.

Abnormalities in developmental milestones in DLP pups.
DLP pups showed deceleration of weight growth after P5 (panel A), worse scores in OFA after P7 (panel B), and scattered days with worse scores in SRT (panel C) and NG (panel D), after P7, compared to controls (CON).
*: P<0.05 compared to controls.

Interictal EEG abnormalities in DLP pups.
Epidural EEG recorded in a pup with spasms show high amplitude spike/polyspike and slow wave activity not associated with any behavioral manifestations. Horizontal bar= 2 sec, Vertical bar= 200 μV.

Thionin stained coronal sections of a P11 pup with spasms showing showing mostly right hemispheric and periventricular injury that includes 1) thinning of the right hemi-cortex and diffuse damage to the 2) corpus callosum fibers, 3) striatum, 4) periventricular areas, 5) septum, 6) hippocampus and 7) thalamus on the right.

Ictal patterns of other seizure types in DLP pups.
Panel A: EEG seizure discharge obtained from depth electrode recording from the entorhinal cortex of a P11 pup with prior spasms. The arrows indicate the beginning and the end of the seizure. During the seizure the rat exhibited behavioral arrest without any clonic movements.
Panel B: Epidural electrode recording in a P9 pup with spasms. During the seizure the pup was displaying “wild running” behavior between the 2 first arrows, followed by behavior arrest (). The electrographic seizure pattern ends at the third arrow.

Flexion spasm in a P9 rat following injections of DOX and LPS at P3 and PCPA at P5. (A) The pup is lying on its side prior to the spasm. (B) The pup raises its head abruptly at the start of the spasm. (C) This is followed by flexion of the trunk, extension of the left forelimb and flexion of the left hindlimb. The head is still raised. (D) The trunk is maximally flexed and there is extension of the left forelimb and both hindlimbs (E) The end of the spasm starts with relaxation of the trunk, however there is continued extension and abduction of the left forelimb. The left hindlimb is still mildly extended. (F) Postictal state. The pup is resting in a mildly flexed position prior to the emergence of a second spasm.

Examples of ictal EEG patterns in P7–9 DLP pups using epidural recordings. The montage utilized here is bipolar: the upper channel is the right frontal-left parietal derivation and the lower channel is the EMG channel to demonstrate the occurrence of spasms (burst of EMG). Spasms in DLP pups showed different EEG ictal correlates, including preictal rhythmic delta (#1) followed by fast (8–9Hz) rhythmic activity (#2) and attenuation (circled) (panel A); fast low amplitude rhythmic activity (#3, panel B); burst of polyspikes (#4) (panel C); polyspikes (#5) followed by attenuation (circled) followed by a second spasm without an EEG correlate (#6) (panel D); high amplitude polyspike and slow wave discharge with attenuation with fast activity electrodecremental response) (#7) (panel E).

Depth EEG recording from the entorhinal cortex during a cluster of 2 spasms in a P9 pup (video 5).
Panel A: The ictal discharge is characterized by the initial appearance of rapid polyspike activity, which precedes the behavioral seizure (inserts B and C, arrowheads, expanded time frame). A movement artifact obscures the onset of the spasm (asterisk). The EEG correlate during the latter part of the spasm consists of a slow wave with overriding polyspikes (inserts D and E, expanded time frame). Panel F: EEG recorded during another spasm. Please note the lack of polyspike activity preceding the spasm. The arrow points to the time the rapid polyspikes seen in the spasms depicted in Fig. 4A, inserts B and C. The different patterns observed at the ictal onset may indicate that there are various generators of the spasms. The second spasm in Figure 4A and the spasm in 4F are followed by a focal discharge (circled). This has also been described to occur in some humans with SIS.

Abnormalities in sociability, grooming behavior, and visuospatial learning in DLP-treated pups with spasms.
Panel A: The description of the social chamber test is described in the . Controls increased in the number of entries to the rat chamber in the presence of a stranger or familiar rat (P<0.05). In contrast, no change in the number of entries was seen in DLP pups with spasms. Hab: habituation; Stra: in the presence of a stranger rat; Famil: in the presence of a familiar rat.
Panel B: DLP pups showed increased grooming behavior reminiscent to stereotypies.
*: P<0.05 compared to controls.
Panel C: During the Barnes maze testing, pups underwent a training period during P16–P19 with 3 trials per day where they were trained to find a target open hole leading to a dark box. Control pups learned the task already by the fifth trial (2^nd day). In contrast, DLP pups were unable to find the target.
*: indicate P<0.05 compared with the controls tested on the same day.
§: indicate P<0.05 compared with same group performance in trial 1.
¶: indicate P<0.05 compared with same group performance in trials 1–3.