We report the case of a 15-year-old boy with a normal perinatal history and psychomotor development. No neurological disease was observed in the family.
The patient's first difficulties began at the age of 9 years and manifested as graphospasm of the right upper limb. Therefore, the patient gradually started to write with his left upper limb, but here too, at the age of 11 years, he developed graphospasm, which made it impossible for him to write with left upper limb. The patient took the tests orally, and when written tests were required, he took them on a computer keyboard. At the age of 11 years, the dystonia extended to the distal parts of the lower limbs, where it was only mild degree and did not limit the patient in normal activities (such as walking). At the age of 15, cervical dystonia (CD) with the rotation of the head to the left began to develop. At the age of 18, oromandibular dystonia (OMD) was associated with a dominant impairment of the mimic muscles, mainly orbicularis oris (manifested as lip puffiness) and tongue (characterized by tongue protrusion). Mild jaw opening was also present, without spasmodic dysphonia and dysphagia.
The patient had an early score of 55 points on the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDS). The patient's greatest handicap was speech impairment resulting from OMD and facial manifestations (resulting from dysfunction of the orbicularis oris muscle). The second severe handicap was CD. The limb dystonia was subjectively assessed by the patient as not severe and not limiting. Objectively, however, it was a dystonia of severe degree (inability to write, play a musical instrument) but with preserved ability to work with a mobile phone and PC. The patient had permanent resting dystonic postures of hands.
Apart from the dystonic manifestations described above, no other central and peripheral nervous systems manifestations were present. The patient’s cognitive status and brain MRI was normal. We carried out genetic testing by means of whole exome sequencing performed on HiSeq4000 platform (Illumina, CA, USA). A novel heterozygous missense variant c.14G>A (p.Cys5Tyr) was detected in the THAP1 gene (Fig. 1). Our finding was first reported by Zech and colleagues among results of multicenter whole-exome sequencing study focused on finding of monogenic causes of dystonia [4].
The presence of this mutation was also determined in the patient's sister (with focal dystonia of the upper limbs arising at the age of 11 years) and their mother (without dystonia).
The patient was treated with biperiden (6 mg per day) for one year; however without any observable effect on dystonia. Higher doses were accompanied by adverse effects, especially dry mouth which made it difficult for the patient to pronounce. The patient received repeated applications of abobotulinum toxin A for CD in the right sternocleidomastoid and the left splenius capitis muscle at a total dose of 500-1,000 IU every three to four months for a period of three years. Its effect, however, gradually weakened and the treatment was stopped. OMD was treated with abobotulinum toxin A to the orbicularis oris (40 IU), depressor anguli oris (10 IU), genioglossus (40 IU) and platysma (40 IU), with an average frequency of application of every three months. This treatment is of mild effect and the patient is still being treated with it.
The patient was indicated for DBS and was subsequently implanted with electrodes into the bilateral GPi (electrodes 3389, stimulator Activa PC, Medtronic). At the time of the surgery, the patient was 20 years old. The operation as such was without any complications. The CT scans of the brain performed immediately after surgery were within normal limits (Fig. 2). On the fourth postoperative day there was a sudden onset of mild expressive aphasia with no paresis of the limbs. The CT scan showed intracerebral hemorrhage along the left electrode, extending from the cortical area at the site of electrode insertion to the end of the electrode in the GPi (Fig. 3). The patient had no proven vascular malformation on preoperative MRI of the brain and cerebral vessels. As a result of this complication, DBS was not initiated until two months after implantation when the speech disorder was completely corrected and the regression of the hematoma was verified during a control MRI examination of the brain. After six months of DBS treatment, we observed a 30% improvement in BFMDS. The patient had an improvement in dystonia in the upper and lower limbs and a slight improvement in CD but OMD remained intact (speech disorder, protrusion of the tongue, facial expressions), which handicapped the patient the most. The patient therefore assessed the surgical outcome as unsatisfactory. Clinical evaluation was performed with DBS stimulation parameters: monopolar setup, frequency 130 Hz, pulse duration 180 ms, stimulation localization –distal contacts in both of the electrodes (type 3389, Medtronic, MN), stimulation intensity 2.9 V on both sides. Subsequently, bipolar setup was tested with different stimulation electrode contacts, high- and low-frequency stimulation (40, 130, 180 Hz), varying pulse durations (60, 90, 120 and 180 ms) and stimulation intensities (1.2 – 3.5 V) and none of these settings achieved the desired effect on OMD and only a minimal effect on CD was noted. OMD partially responded to abobotulinum toxin A injections. Due to the insufficient effectiveness of DBS, we considered the possibility of posthemorrhagic structural changes of the tissue in the vicinity of the stimulation contacts of the left electrode and we performed a control MRI of the brain one year after implantation. The examination showed a posthemorrhagic cortico-subcortical pseudocyst located out of electrode contacts. (Figs. 4 and 5).
Two years after DBS implantation, the patient experienced the first generalized epileptic tonic-clonic seizure with an unknown onset. The control MRI scans of the brain were without any changes. An EEG showed episodes of bifrontal rhythmic delta waves with left-side amplitude accentuation and abortive spike-wave complexes (Fig. 6). One year later, the patient experienced a second generalized tonic-clonic seizure and subsequently treatment with levetiracetam was started at a dose of 1000 mg daily.
The patient is nowadays 23 years old (three years after DBS implantation) and his BFMDS score is 55 points (the same as preoperative). There is a severe degree of CD approximately in the same extent as before the implantation, severe OMD which has slightly progressed compared to the preimplantation condition and very mild dystonia at the distal region of the upper and lower limbs which have improved with DBS. The patient is treated with levetiracetam and abobotulinum toxin A injections into the oromandibular muscles with a partial effect. Speech impairment is still a major determinant of the patient’s quality of life. Cognitive functions are normal.