Dear Editor,

A 19-month-old male with acute febrile illness and respiratory distress with subsequent continuous jerky movements was referred to us. The parents reported abnormal movements beginning in the left upper limb, followed by the left lower limb over the next two days, and spreading to the whole body, including the tongue, eyes and head, by the end of the week. These movements increased during periods of crying or agitation and subsided during sleep. He was the third child born to non-consanguineous parents and was exclusively breastfed. He had preexisting mild developmental delay. On examination, he was underweight (weight 5 kg, <-3z score); exhibited stunted growth (length 67 cm, <-3z score) and microcephaly (head circumference 42.8 cm, <-3z score); and had a dull, expressionless face. The patient presented with pallor, sparse hypopigmented hair, and hyperpigmentation of the skin, especially over the dorsum of the hands and feet and bony prominences (Figure 1). He exhibited near-continuous, involuntary, abnormal, hyperkinetic shaking; back-and-forth movements predominantly in the left half of the body; and ipsilateral “twitching” of the eye and an angled mouth. These movements resembled coarse tremors in the distal limbs, head, and tongue typical of infantile tremor syndrome (ITS), but associated dystonic posturing of the left upper limb and proximal movements resembling myoclonus were also observed. The patient exhibited associated regression of language and a “bleating” cry. The child remained conscious during these movements, which were reduced during sleep (Supplementary Video 1 in the online-only Data Supplement). Due to the predominant involvement of the left side of the face and body, which was initially interpreted as focal-onset, tonic‒clonic twitching, a provisional diagnosis of ITS with epilepsia partialis continua was considered.

Investigations revealed anemia, low serum vitamin B12 level, elevated homocysteine level, and low vitamin D level. Video-electroencephalography indicated that these movements were nonepileptic (Supplementary Video 2 in the online-only Data Supplement). Magnetic resonance imaging of the brain revealed diffuse cortical atrophy. The patient received daily intramuscular B12 injections as well as nutritional rehabilitation. His tremors and general condition substantially improved after two weeks of therapy. At the 6-month follow-up, he had significantly improved (Supplementary Video 1 in the online-only Data Supplement).

ITS, also known as neurocutaneous infantile B12 deficiency syndrome, is a clinical disorder characterized by mild developmental delay or neuroregression; pallor; coarse tremors of the head, tongue, and limbs; and pigmentary changes in the skin and hair [1,2]. ITS is predominantly observed in exclusively breastfed infants of vegetarian mothers but has also been reported in infants of nonvegan mothers [3]. ITS classically presents between 6–24 months of age with listlessness, apathy, sparse and light-colored hair, and hyperpigmentation over the dorsal aspects of the hands, nail folds, feet, knees, ankles, buttocks, and axillae [1]. Intercurrent illnesses are known to trigger acute neurological deterioration in these infants [4].

Involuntary movements in untreated infants with ITS include tremors, hypokinesia, myoclonic jerks, choreoathetoid movements, titubation, and classic “batwing” dystonias [3,4]. The most characteristic feature of ITS is tremors, which are usually absent in the early stage of illness and precipitated by infections and stress [1]. Tremors in ITS are coarse and jerky (myoclonus-like) and involve the facial, perioral, lingual, pharyngeal, and laryngeal muscles and distal limbs [1,5,6]. The term “tremor-myoclonus” has also been used for these movements [4]. Myoclonus has been reported in ITS patients and may worsen with vitamin B12 therapy [1,4,7]. The index case had a combination of tremors with dystonia and myoclonus with a predominant focal presentation. The onset of tremor is usually focal and intermittent, and tremors rapidly progress to generalized involvement that may be asymmetrical and multifocal [1,5,6]. The tremors typically disappear during sleep but may persist at low intensity in severe cases [1]. The characteristic “goat bleating” sound during vocalization/crying is due to tremulousness caused by the involvement of the lingual, pharyngeal, and laryngeal muscles [1,4].

When associated with twitching or a prominent jerky appearance, these tremors are often confused with epilepsia partialis continua, as in the index case. Clinically, a tremor is an involuntary, rhythmic, oscillatory movement that can be differentiated from a seizure by its rhythmicity and lack of autonomic changes and response to antiepileptic drugs. Tremors can also be induced by stimulation and stopped by restraining the affected limb. Video-electroencephalography can be used to differentiate the two conditions and prevent unnecessary therapeutic trials. The disorder, including tremors and hyperpigmentation, responds dramatically to vitamin B12 therapy and nutritional rehabilitation [1,6]. Tremors usually resolve within 1–2 weeks of treatment initiation and completely disappear after 3–4 weeks, but resolution of the skin and hair changes may take months [1].

In conclusion, focal tremors in ITS patients can mimic epilepsia partialis continua. The pattern of movement and electroencephalogram can help to differentiate tremors from seizures. Recognition of this entity is essential because it has a favorable response to therapy and affects long-term neurological outcomes. In this report, we underscore the critical importance of considering treatable neurometabolic syndromes in the differential diagnosis of movement disorders.

Supplementary Materials

Video 1.

Segment 1: The video show near-continuous, involuntary, abnormal, hyperkinetic shaking; back-and-forth movements predominantly in the left half of the body; and ipsilateral “twitching” of the eye and an angle of the mouth. These movements resembled coarse tremors in the distal limbs, head, and tongue with additional dystonic posturing of the left upper limb (resembling focal bat-wing dystonic tremors) and proximal myoclonus. The child remained conscious during these movements, which were reduced during sleep. Due to the predominant involvement of the left side of the face and body, these tremors mimicked the focal-onset, tonic‒clonic twitching observed in epilepsia partialis continua. Segment 2: The last part of the video (follow-up) shows a remarkable recovery of the patient with recovery of mile-stones after six months.

Video 2.

Video-electroencephalogram showing persistent focal-predominant movements on the left side that diminished during light sleep (without sedation) and were recorded by electroencephalogram as nonepileptic.

Notes

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

None

Author Contributions

Conceptualization: Arushi Gahlot Saini. Data curation: all authors. Formal analysis: Tonyot Gailson, Pradeep Kumar Gunasekaran, Chaithanya Reddy. Investigation: all authors. Methodology: all authors. Project administration: Arushi Gahlot Saini. Resources: all authors. Software: all authors. Supervision: Arushi Gahlot Saini. Validation: Arushi Gahlot Saini. Visualization: Arushi Gahlot Saini. Writing—original draft: Arushi Gahlot Saini, Tonyot Gailson, Pradeep Kumar Gunasekaran. Writing—review & editing: all authors.

Acknowledgments

None

Figure 1.

Clinical photograph of the index case showing irritability (A), sparse hair (B), and hyperpigmentation (C).

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