A 66-year-old male presented with gradually progressive weakness of the left hand and leg for 4 years. Initially, he noticed mild weakness in his left hand grip and some difficulty walking in the form of dragging the left foot with poor ground clearance, which was gradually progressive and started to affect his activities of daily living. He also complained of stiffness in the left leg for the same duration. There was no history of bladder or bowel involvement, thinning of limbs or atrophy of muscles, fasciculation or sensory involvement. On examination, he was conscious and obeying commands. Power in the left upper and lower limbs was Medical Research Council grade 4+, and deep tendon reflexes were brisk on the left side. Tone was increased on the left upper and lower limbs, and sensory examination was normal. Cerebellar signs were present on the left side in the form of dysdiadochokinesia, impaired finger–nose test and impaired heel–shin test. Routine blood investigations were normal including TSH and vitamin B12 level. Nerve conduction study and electromyography were normal. Brain MRI showed mild atrophy of the right cerebral peduncle and reduced bulk of the right corticospinal tract in comparison to the left corticospinal tract (Figure 1A–D).

Figure 1.

Brain MRI axial T1-weighted image (A), axial Fluid Attenuated Inversion Recovery (FLAIR) image (B) and axial T2-weighted image (C) demonstrate mild atrophy of the right cerebral peduncle (solid arrow) compared to the left cerebral peduncle (dotted arrow). Coronal DTI image (D) reveals reduced bulk of the right corticospinal tract (solid arrow) in comparison to the left corticospinal tract (dotted arrow). Additionally, a few prominent T2 hyperintense Virchow–Robin spaces are observed in the bilateral cerebral peduncles (C).

In 1990, Charles Mills first described cases of progressive spastic hemiparesis starting from lower limbs without sensory involvement. Postmortem examination of one such patient, who died subsequently from tuberculosis, showed degeneration of the pyramidal tracts without involvement of Betz cell and anterior horn cell.^{Reference Jaiser, Mitra, Williams and Baker1,Reference Huynh, Tu, Mahoney, Schwartz and Kiernan2} About 23 cases of Mills syndrome have been described since then in the form of case reports.^{Reference Jaiser, Mitra, Williams and Baker1,Reference Huynh, Tu, Mahoney, Schwartz and Kiernan2} It is clinically different from other motor neuron diseases (MNDs) like primary lateral sclerosis (PLS) and amyotrophic lateral sclerosis (ALS). It has an onset in middle to old age and is characterized by only upper motor neuron involvement throughout its course. In most patients, even after 15 years of follow-up, it remained strictly unilateral; however, in about 30% of cases, bilateral involvement has been seen. Some of the authors consider it as a hemiparetic variant of PLS. However, predominant lower limb involvement and extremely asymmetric course even in advanced stages contrast with PLS. The absence of positivity for TAR-DNA binding protein 43 in a case of Mills syndrome also distinguishes it from MND.^{Reference Fernandes, Turner, Zeidler, Smith and Davenport3}

The diagnosis of Mills syndrome is essentially clinical, and other mimickers like stroke, Chiari malformation, primary progressive multiple sclerosis, neurosyphilis, hereditary spastic paraplegia, adrenomyeloneuropathy and tropical spastic paraplegia should be excluded. We also found mild cerebellar signs on the left side, which is not a typical feature of Mills syndrome. These subtle cerebellar signs can be explained by the complex connections between the corticospinal tract and the cerebellum. Although cerebellar involvement has not been reported in Mills syndrome, subtle cerebellar involvement has been seen in PLS and ALS.^{Reference Kabiljo, Iacoangeli, Al-Chalabi and Rosenzweig4}

Brain MRI is normal in Mills syndrome. Our case reported unilateral midbrain atrophy, which is rarely described in the literature.^{Reference Huynh, Tu, Mahoney, Schwartz and Kiernan2,Reference Wang, Xu and Chen5} In our case, there was atrophy of the right cerebral peduncle, and Diffusion Tensor Imaging (DTI) confirmed reduced bulk of the right corticospinal tract as compared to the left corticospinal tract. In the absence of well-defined diagnostic criteria, pointers such as midbrain atrophy should be carefully looked for as they can suggest the diagnosis of this rare condition.

Clinicians should be aware of this syndrome, and unilateral midbrain atrophy involving the cerebral peduncle may be a pointer to the diagnosis.