A 33 year old woman who at the end of 2002 went to the emergency department complaining of insomnia and fatigue. She was diagnosed with anxiety disorder and was discharged. Six weeks later she was readmitted to the hospital with weakness, generalized myalgia, and a tingling sensation in her extremities. Given the early recurrence, the neurology department was consulted. In the neurological exam her mental state was normal, her pupils were normal symmetrical, and reactive to light. There was no facial asymmetry and the other cranial nerves were normal. Muscle tone was increased in bilateral lower extremities. Grade II-III spasticity was diagnosed, as well as decreased vibratory sensitivity and bilateral Hoffman sign (involuntary flexion movement of the index finger when the examiner flicks the fingernail of the middle finger down), bilateral Babinski sign (plantar flexor response) and positive Romberg sign, with a tendency to fall to the right. Routine blood test was normal, except for cholesterol level (268 mg/dL). Magnetic resonance imaging (MRI) detected seven of demyelinating lesions of various sizes, especially periventricular and supratentorial and some infratentorial, as well as cortico-subcortical atrophy. No signs of progressive multifocal leukoencephalopathy were visualized.
In mid- 2003 she had an optical neuritis (left retrobulbar type) visual outbreak, with a complete recovery, and 4 years later a spinal outbreak that presented itself as a paraparesis.
The patient began treatment with beta-1a interferonin 2008 and because of her lack of response to the treatment due to some outbreaks and an increase in EDSS of up to a score of 5.0, in 2009 it was considered convenient to change to Natalizumab as a high activity treatment. She continued that treatment for 7 years but the persistence of attacks, although spread over the time, and the progression of associated disability (EDSS score 5.5), indicated a further change to another high efficiency therapy, i.e., Alemtuzumab, with which she completed the two cycles indicated on the data sheet. During her neurological examination the prominent features were: a visual optical neuritis-type aftermath, a minimal oculomotor alteration, invalidating spastic paraparesis, right hemiparesis, and sphincter disorders which currently would be defined by a score of 6.0 on the EDSS scale.
Standing out as comorbidities were: depression as a reaction to her illness, notable spasticity, fatigue and joint pain, all of them being treated pharmacologically for the past 5 years.
Three years ago, given her disability and lack of response to the symptomatic treatment prescribed, rTMS treatment was proposed, which she accepted. Based on the results obtained with TMS in previous clinical studies carried out in patients with MS, as well as in its equivalent experimental model in rats (experimental autoimmune encephalomyelitis, EAE) and in other neurodegenerative diseases, the main objective was to improve the degree of disability in this patient. We also wanted to examine her evolution at the neuropsychological level and her biomarkers of oxidative damage in blood, in order to look for links between these aspects.
Cycles of a daily session of rTMS were prescribed. These were grouped into 5 consecutive days, followed by 3 weeks resting, until 14 cycles (70 sessions in all) were completed, spread over 14 months. The stimulation was applied at 3 cm in front of the Cz point in the craniocaudal axis. The stimulation power was established as a function of the motor threshold of the patient, representing 90% of its total value. It was administered as a continuous stimulation with a frequency of 1 Hz during a span of 600 s in each session.
In each session, we follow this protocol in two steps:
First step: Obtaining the Motor Evoked Threshold at Rest: the patient had her threshold evoked motor calculated at rest, by stimulation of the motor cortex in the left hemisphere, evoking electromyographic responses (EMG) in the contralateral muscles, called motor evoked potentials (MEP). The threshold of motor excitability at rest (TM) is defined as the minimum intensity (expressed as the percentage of the maximum output power of the stimulator) capable of producing a reproducible MEP in a resting muscle in 50% of 10 shots.
Second step: Administration of the Transcranial Magnetic Stimulation: A Rapid 2 Magstim device (Magstim Co. , Whitland, Carmarthenshire, Wales) equipped and connected to a figure-of-eight coil of 70 mm was used. This equipment is used to calculate the TM and the percentage of it to which the treatment will have to be applied. The selection of the specific point of stimulation in the Supplementary Motor Area (SMA) was sufficiently anterior to prevent the propagation of the impulse from triggering the muscular contraction of the shoulders, trunk, and lower limbs. The position of the coil was marked on the scalp to ensure consistent placement of the coil throughout the experiments; the patient was fitted with a lycra cap on which to indicate and also mark the exact stimulation point, as well as on which to place and hold the coil during the therapeutic session. The coil was oriented toward the posterior area in order to trigger a postero-anterior current. The TM was calculated in relation to the evoked potential and according to international standards. Based on it, TM was defined as the lowest stimulus intensity that elicited a minimum MEP amplitude of 50 mV in the completely relaxed FDI muscle in at least 5 out of 10 consecutive trials.
During this treatment time, periodic physical and neurocognitive evaluations were made, as well as blood analyses (Table 1). The neuropsychological tests were generally orientated toward assessing the patient's cerebellar and motor functions (as in the 9 HolePeg Test and the Timed 25-Foot Walk) and her short and medium term mnesic capacity (as is the case of the Selective Reminding Test, 10/36 Spatial Recall Test, Symbol DigitModalities Test, Paced Auditory Serial AdditionTask and Word List Generation Test). Generally speaking, the results of the tests showed an improvement in the patient's motor and neurocognitive abilities (displaying an increase in the scoring scales), as well as a lower degree of disability (falling from 6 to 5 points in the EDSS scale as from the second month of treatment with rTMS) (Figure 1) and a better perception of her health in relation to the impact of the disease on it (showing a drop in the EQ-5D-5L and MSIS-29 scales scoring) (Figure 2). This improvement, according to the evaluation scales, was produced practically starting from a short time after the beginning of the treatment (at between 4 and 8 months), and was maintained the whole time. Only a small increase in Timed 25-Foot Walk was observed; in the first four evaluations it lasted 12 s and in the last one 15, which could correspond to a slight slowing down of her ambulation.
The laboratory study took into consideration routine biochemical magnitudes and oxidative stress parameters (Table 2). It was carried out at two moments: half-way through and at the end of the treatment period. In both laboratory studies a very slight, or clinically irrelevant variation was generally observed, although the oxidative stress parameters displayed a notable change, with a tendency toward an antioxidant status.