High T2 Signal in Primary Lateral Sclerosis Supports the Topographic Distribution of Fibers in the Corpus Callosum: Assessing Disease in the Primary Motor Segment

SUMMARY: PLS is a disease of the UMN, distinguished from ALS in prognosis and absence of LMN signs. We present, to our knowledge, the first conventional MR imaging visualization of the callosal motor segment, a concept previously supported by primate models, electrophysiologic studies, and postmortem examinations. Modification of the Witelson topographic scheme of the CC is supported by MR tractography. On the basis of 2 cases of PLS, we present conventional imaging confirmation of the revised topographic scheme of fiber distribution across the CC.

P LS is a progressive pure UMN disorder first described in the late 1800s by Charcot and Erb; it can be distinguished from ALS by its characteristic absence of LMN signs. Both conditions arise sporadically, and both have been linked to specific mutations, 1 though PLS is far less common than ALS, constituting as little as 1% of motor neuron diseases. 2 Since diagnostic criteria for PLS were first proposed, 3 reports have questioned its distinction from ALS, instead viewing PLS as an indolent variant with an exclusively UMN presentation. [4][5][6] However, further case series 7,8 have underscored the association between longer survival time and UMN-predominant disease, making the distinction between ALS and PLS clinically relevant and suggesting at least a separate syndromology.
ALS and PLS share MR imaging features such as T2 hyperintensity within the CST, [9][10][11] atrophy of the motor and premotor cortex, 3,12 MR imaging signal-intensity changes within the precentral gyrus, 10 and decreased FA on tensor imaging of the descending motor pathway. 13,14 Furthermore, PLS and ALS both manifest involvement of the CC, including loss of contralateral motor inhibition on behavioral testing, 15,16 decreased FA on DTI, 17,18 and an isolated report of callosal T2 hyperintensity in a case of ALS. 19 We present 2 cases of PLS demonstrating increased T2/FLAIR signal intensity within the posterior body of the CC and discuss their relevance to understanding the topographic distribution of cortico-cortical interhemispheric projections.

Case Reports
The 2 patients presented herein were referred from the neurology department with a diagnosis of PLS. For both patients, clinical and laboratory findings were consistent with a diagnosis of "clinically pure PLS" according to the diagnostic criteria put forth by Gordon et al. 7

Case 1
A 50-year-old man presented for adjustment of his medications. His medical history was significant for the onset of progressive right-leg weakness beginning in his late 20s, followed 3 years later by right upper extremity weakness. Within 5 years, spasticity and weakness of all 4 extremities prevented the patient from working. Electromyography was negative for lower motor neuron involvement. As the disease progressed, the patient became wheelchair-dependent. One year prior, he underwent bilateral tendon release surgeries for Achilles contractures.
His examination was significant for hyperreflexia and spasticity in all 4 limbs, minimal voluntary movement of his upper extremities, lower extremity paresis, and dysarthria.

Case 2
A 59-year-old man, diagnosed previously with multiple sclerosis presented to the neurology clinic for a second opinion. He experienced the onset of right-hand weakness at 39 years of age, and during the next decade, developed right-leg weakness, dysarthria, and chronic urinary urgency. Neurologic examination in the clinic demonstrated right-sided spasticity, right pronator drift, dysarthria, frontal release signs, and global hyperreflexia. Ankle clonus and Babinsky signs were elicited bilaterally. Lumbar puncture was negative for oligoclonal bands.

Results
MR mages were acquired on a Magnetom Sonata 1.5T scanner (Siemens, Erlangen, Germany).

Region-of-Interest Analysis
Representative axial FLAIR images from patients 1 and 2 were selected, and regions of interest were generated within pathologic subcortical white matter (increased T2 signal) and normal-appearing ipsilateral white matter. A midsagittal FLAIR image from patient 2 (Fig 5A) was used for region-of-interest analysis of the CC: Regions of interest were generated within the pathologic white matter in the posterior body and the normal-appearing white matter in the anterior body. Measurements of region-of-interest area and signal intensity are displayed in the Table.

Discussion
The CC is the largest white matter tract in the human brain. Knowledge of its functional anatomy derives from several    lines of inquiry. Aspects of callosal function are revealed through observation of individuals who have undergone callosotomy for intractable seizures, patients with so-called "split-brain." Comparison of these patients with those with focal callosal lesions has led to inferences about the organization of transcallosal fibers. Autoradiographic techniques in primates have visualized transcallosal projections of the primary motor cortex to homotopic and heterotopic areas of the contralateral precentral gyrus. 20 Postmortem studies in humans have revealed a topographic distribution of fibers in the CC [21][22][23] and have demonstrated heterotopic and homotopic transcallosal projections. 24 Transcranial magnetic stimulation, initially a technique used to assess CST integrity, 25 has been applied to the study of cortico-cortical interactions. Meyer et al 15 demonstrated that stimulation of the primary motor cortex inhibits the contralateral motor cortex, a finding diminished or absent in patients with callosal lesions. By comparing patients with a range of focal callosal lesions, the investigators deduced that motor inhibitory pathways occupy the posterior body of the CC. 26 Loss of motor inhibition explains the finding of increased involuntary contralateral comovements in patients with ALS 16 and is consistent with decreased FA values in the CC of patients with ALS and PLS. 17,18 The Witelson scheme for partitioning the midsagittal CC had    been widely accepted for more than a decade on the basis of data derived from humans and nonhuman primates. The scheme has been challenged by data from DTI-based tractography, 27 which modifies the standard scheme (Fig 9), relocating the Witelson motor region (II, anterior midbody) more posteriorly within the CC (III, posterior body). Figure 5B depicts the primary motor segment of the CC, as defined by the tractography data of Hofer and Frahm. 27 Figure 5C is a simple overlay of the images in 5A and 5B, localizing the midsagittal MR imaging findings from patient 2 to the callosal motor segment. We presented 2 cases of PLS, a degenerative disease of the UMN, which demonstrate volume loss and high T2 signal within the posterior body of the CC, corresponding to the primary motor segment in the Hofer and Frahm revised topographic scheme of fiber distribution within the midsagittal CC. 27