A brain MRI showed bilateral iron deposits in both SN and globus pallidus (GP), whereas 123I-FP-CIT single-photon emission CT (SPECT) brain imaging uptake was bilaterally abnormal (Fig. 1). Genetic testing for neuroferritinopathy (ferritin light chain 1 [FTL1] gene), pantothenate kinase (PANK)-associated neurodegeneration (PANK2 gene) and phospholipase A2, group VI (PLA2G6)-associated neurodegeneration (PLA2G6 gene) was negative. After 3 years of follow-up, the patient had not developed apparent freezing of forward gait or any other new neurological symptoms, and his backward freezing is clinically stable. No change was evident on the repeat MRI scan.
Figure 1. (A) T2-weighted (1.5 Tesla) axial and coronal brain MRI sequences (left images) that show bilateral GP hypointensity with a small area of hyperintensity, compatible with the “eye of the tiger” sign. Gradient echo axial brain MRI sequences (central and right images) showing bilateral symmetrical hypointensities in SN and GPi that correspond to iron deposition. (B) 123I-FP-CIT SPECT brain imaging showing lack of uptake in both putamen nuclei, predominantly the left, and mild hypocaptation of the left caudate nucleus.
Several genes have been described to cause neurodegeneration with brain iron accumulation (NBIA): FTL1, PANK2, PLA2G6, ATP13A2 (PARK9), fatty acid 2-hydroxylase (FA2H; FA2H-associated neurodegeneration), CP (aceruloplasminemia), WDR45 (X-linked dominant NBIA), and C19orf12 (mitochondrial membrane protein-associated neurodegeneration). As mentioned above, we ruled out the first three of the former entities. The remaining conditions usually present, unlike our patient, as progressive broader neurodegenerative syndromes with childhood or young-adult onset. Aceruloplasminemia can start in the elderly, but is usually accompanied by serum abnormalities such as undetectable ceruloplasmine or elevation of ferritin, which were not found. Therefore, thus far we consider our patient to be affected by an unclassified late-onset form of NBIA, which can account for 50% of all cases.
We would like to stress the semiologic interest of the case, because we consider that our patient's disturbance in walking backward agrees, except for the direction of progression, with the working definition of FOG proposed by the International Parkinson and Movement Disorder Society: “brief, episodic absence or marked reduction of forward progression of the feet despite having the intention to walk.” The experts highlighted that “focused attention and external stimuli (cues) can overcome the episode.” Thus, our patient's problem with backward gait overlaps with the description of “forward FOG,” including the ability to overcome freezing using an auditory cue; consequently, we conclude that our patient suffered from primary backward FOG, a clinical feature, to our knowledge, not previously described in the literature as the main complaint. In our experience backward FOG can frequently be observed on pull testing, in patients who suffer from forward FOG, but we have not remarked on such a disassociation with backward freezing and frequent backward falls being so prominent, in comparison to forward FOG. FOG, in the context of a loss of psychic autoactivation, is a typical feature of bilateral pallidal lesions with patients having no rigidity and relatively little akinesia. The GP internus (GPi), together with the SN reticulata, represent the basal ganglia output to the mesencephalic locomotor region, a midbrain area involved in locomotion and step eliciting. Our patient has damage of these output structures related to iron deposits. Why he predominantly presents with backward gait disturbance remains speculative. Difficulties in walking backward have been already reported on in a patient diagnosed with neuroferritinopathy, a form of NBIA. The investigators discussed FOG, but eventually ruled it out, because of the absence of its episodic nature, which is indeed an important feature of FOG in the classification of gait disturbances. However, their published video also reveals mild FOG on turning. We suggest that both patients suffer from backward FOG, because in both patients the difficulty in initiating backward gait corresponds to the so-called “akinetic freezing” occurring at movement initiation. And, indeed, the abnormality in pull test observed in both patients could be attributed to this initiation failure, rather than to postural reflexes impairment.
There are very few studies of backward gait in parkinsonism and exclusively in Parkinson's disease, demonstrating disturbances that transcend forward walking deficits, but they do not mention freezing of backward gait.
We propose that the FOG working definition should not ignore backward progression and that backward FOG should be systematically looked for during pull test for evaluation of postural reflexes, but also on starting backward gait, especially in patients with parkinsonism with a complaint of backward falls.