Background

Superficial siderosis (SS) is a rare disease caused by hemosiderin deposition in central nervous system and typically leads to neurological dysfunction and progressive irreversible symptoms. Multiple Sclerosis is most common demyelinating disease which usually courses with relapses and remissions but some patients can have a progressive course. Progression in MS patients is defined as a worsening of functional systems over one year.

We are presenting MS patient since 1994 who developed in last three years a progressive ataxia which was initially attributed to MS progression, nevertheless MRI showed hypointensities on cerebellum that led us to diagnose SS. Recognizing this entity is important because it could be a cause of pseudo progression in MS patients.

Objectives

We want to disclose the superficial siderosis as an unusual cause of pseudo-progression in patients affected by multiple sclerosis.

Methods

A 63 year-old woman with history of relapsing-remitting MS (RRMS) treated with Glatiramer acetate. She was stable until 2017, but since then she started to notice clumsiness of her both hands and difficulties to walk. She even had some falls because of unsteady gait.

Her Expanded Disability Status Scale (EDSS) passed from 2.0 to 4.5 due to worsening of cerebellar functional system and the using of a cane for walking. Over next three years she had progressive impairment of gait and coordination of all limbs. Sensorineural hearing loss of unknown cause was also diagnosed during this time. On last neurological examination she presented mild cerebellar dysarthria, moderate ataxia of all limbs, ataxic gait and need to walk with bilateral support. Other signs of the neurological examination were mild decrease of vibration and brisk reflexes on lower extremities. Currently her EDSS is 6.5

A cerebellar relapse was ruled out as cause of her symptoms because of progressive course, no recovery after steroids and no evidence of new T2 lesions on cerebellum. A RRMS turning into SPMS was initially accepted as responsible of her worsening.

Results

A comprehensive approach was performed, as there was an almost exclusive deterioration of the cerebellar functional system. So, a new brain MRI was requested and hemosiderin effect was seen along cerebellar folias. This finding was the key to diagnose superficial siderosis.

A neuroaxis MRI evaluation was done and there was no evidence of SS in other parts of CNS nor evidence of chronic bleeding that causes SS on cerebellum.

We proposed to initiate treatment with Deferiprone but the patient rejected to take it after we exposed lack of clear effectiveness. She is still being treated with Glatiramer acetate for MS.

Conclusions

Superficial siderosis can be a mimic of progression in patients affected by multiple sclerosis, that is why we recommend to take into account this entity in those patients with progressive worsening of walking secondary to exclusive affectation of cerebellar functional system.

Background

Neuromyelitis optica spectrum disorders (NMOSD) are mostly relapsing autoimmune inflammatory disorders of the central nervous system. Hallmark features of NMOSD include acute attacks of bilateral or rapidly sequential optic neuritis or transverse myelitis. Attacks most often occur over days, with variable degrees of recovery over weeks to months

Other suggestive symptoms include episodes of intractable nausea, vomiting, hiccups, excessive daytime somnolence or narcolepsy, reversible posterior leukoencephalopathy syndrome, neuroendocrine disorders, and seizures

The discovery of AQP-4 antibodies supposed a breakthrough for understanding NMOSD. Recently, MOG antibodies have been also related to this entity. However, about 10-50% of NMOSD patients are still seronegative. These patients are a heterogeneous subgroup that may be associated with other autoantibodies

Objectives

To identify main clinical and radiological characteristics

To recognize differences between seropositive and seronegative NMOSD patients

To evaluate safety and effectiveness of Rituximab

Methods

We presented 12 patients diagnosed of NMOSD according revised consensus criteria published in 2015 at Unit of Neuroimmunology and Multiple Sclerosis Unit of Girona, Spain

The data were collected during the course of clinical care. We focused on medical history, neurologic symptoms, MRI features, CSF findings

Rituximab response was assessed using the annualized relapse rate (ARR)

Results

Disease-onset form: optic neuritis 7 (58,3%) 1 of them had bilateral optic neuritis; myelitis 4 (33,3%); brainstem syndrome 1 (8,3%)

Abnormal laboratory findings: 2 patients had positivity for lupus anticoagulant, 1 for TPO-Ab and 1 for ANAs

8 patients were seronegative NMOSD

6 patients (50%) had cognitive impairment

CSF findings: 8 patients had CSF abnormalities include pleocytosis and elevated protein levels. Oligoclonal bands were positive in 4 patients

4 patients were positive for antibodies: AQP-4= 2 / MOG= 2

MRI findings: 4 patients had brain MRI abnormalities that matched with NMOSD pattern, rest of patients had normal or unspecific MRI. Longitudinally extensive spinal cord lesions were observed in 7 patients. Cervical and thoracic segments were most affected

4 patients had positivity for other antibodies. 3 of them are seronegative NMOSD

Of 4 seropositive patients, 3 had cognitive impairment

Of 4 patients with presence of CSF oligoclonal bands, 3 were seronegative NMOSD

ARR before Rituximab: 1,25 and ARR after Rituximab: 0,27

No patient had serious adverse events after Rituximab treatment. Rituximab was discontinued in 1 patient due to an allergic reaction

Conclusions

Seronegative NMOSD has a prevalence up to 60% and it could be related with presence of other serum antibodies and with positivity for CSF oligoclonal bands

Cognitive impairment is frequent in NMOSD and can be more prevalent in seropositive patients

Rituximab is safe and effective to reduce ARR

Background

Memory impairment affects more than 50% of patients with multiple sclerosis (MS), strongly impacting their life quality. Previous studies have suggested a correlation between functional hippocampal alterations and episodic memory impairments in MS. Nevertheless, these studies are rarely focused on preclinical nor initial stages of the disease, essential to develop targeted interventions to prevent or delay memory impairment in MS.

Objectives

To investigate episodic memory performance and hippocampal functional connectivity abnormalities in the preclinical and initial stages of MS.

Methods

Cross-sectional study of 50 subjects: 30 healthy controls and 20 patients with clinical and radiological isolated syndrome (CIS/RIS) (n=13 and 7, respectively). Episodic memory capabilities were assessed with a modified version of Rey Auditory Verbal Learning Test (RAVLTm): introduction of two recognition trials in the five learning trials. Moreover, participants underwent a magnetic resonance imaging session on which resting-state sequences were acquired. Regression models were used to evaluate between-group differences in memory capabilities. Two-sample t-tests models were used to assess whole-brain differences in the seed-based functional connectivity (FC) of the bilateral hippocampus. All analysis were controlled for gender, age, educational level and presence of anxiety and/or depressive symptoms.

Results

No between-group differences emerged in the sum of the words of the learning trials (p=0.164), the delayed recall trial (p=0.193) nor the three recognition trials as measured by discriminability index (d’) (p=0.775, p=0.954, p=0.395, respectively) and Criterion Level (C) (p=0.860, p=0.864, p=0.858, respectively). Nevertheless, compared to controls, CIS/RIS showed higher FC in the hippocampi-right angular gyrus network (t= 5.18, p<0.001).

Conclusions

Prior any sign of episodic memory dysfunction in preclinical and initial stages of MS, higher FC in the hippocampi-right angular gyrus are detected. These findings could be explained as compensatory mechanism used by CIS/RIS to achieve the same performance in episodic memory task as healthy controls. At the same time, such FC increase could be an early sign of future episodic memory problems.

Background

Memory impairment is commonly found in multiple sclerosis (MS), presented in between 40 to 75% of patients. It is accepted that hippocampus plays a critical role in memory function therefore studying this brain structure is crucial to understand the nature of memory deficits. However, there is a lack of knowledge regarding how functional connectivity changes in memory-related brain regions, such as the hippocampus, exist between MS subtypes.

Objectives

To investigate hippocampal resting-state functional connectivity changes between MS subtypes and healthy controls, and associations with the presence of total white matter (WM) lesions.

Methods

30 healthy controls and 78 MS patients (34 relapsing-remitting (RRMS)), 24 primary or secondary progressive subtypes (PMS) and 20 clinical or radiological isolated syndrome (CIS/RIS)) underwent a magnetic resonance imaging session. Univariate ANOVA models in SPM12 were used to assess whole-brain differences in the seed-based functional connectivity (FC) of the bilateral hippocampus, between controls and MS subtypes. Regression models then assessed whether the FC strength in the identified hippocampal networks showed a significant association with total WM lesions.

Results

Mean total WM lesion volume was different among MS subtypes (F=18.493; p<0.001), with PMS showing the highest lesioned volume (16.32±14.09ml), followed by RRMS (8.93±9.46ml) and CIS/RIS (2.07±2.67ml). Compared to controls, both the PMS and RRMS showed lower FC in the hippocampi-right middle frontal gyrus network, while RRMS additionally showed lower FC with the rostral anterior cingulate cortex. Conversely, CIS/RIS showed higher FC in the hippocampi-right angular gyrus network. The lower FC in the hippocampi-right middle frontal gyrus network in PMS and RRMS was also significant compared with CIS/RIS, with PMS additionally showing lower FC in the hippocampi-dorsomedial frontal cortex. Finally, RRMS showed lower FC in the hippocampi-left insula network when directly compared to PMS. The strength of FC in the hippocampi-dorsomedial prefrontal cortex network was negatively associated with the total WM lesion volume (R²= 0.085, F= 6.76, p= 0.011) across the MS patients.

Conclusions

Hippocampal FC differences exist depending on MS subtypes, and the highest presence of total WM lesions impacts the FC with medial prefrontal cortex regions. Future studies are necessary to link such hippocampal changes with specific memory impairment.

Background

Multiple sclerosis (MS) can cause progressive walking impairment that contributes to disability and reduced quality of life. Dalfampridine, a voltage-dependent potassium channel blocker, has been shown to improve walking in patients with MS, as demonstrated by an increase in walking speed.

Dalfampridine is approved as symptomatic treatment of impaired mobility in MS patients. Recently, it has been published dalfampridine could have an effect on other functional systems (FS) not directly related to ambulation.

Objectives

To demonstrate the dalfampridine effect on different FS.

To identify wether the impact on the different FS stabilizes the EDSS.

To establish correlations between different scales used to measure dalfampridine effectiveness and FS scores.

Methods

We collected 22 patients diagnosed of either relapsing-remitting, secondary progressive or primary progressive MS according Mc Donald´s criteria 2010 responsers to dalfampridine for at least one year.

Dalfampridine effectiveness was evaluated by Timed 25 foot-walk (T25-FW), Timed Up and GO (TUG), and Two minutes walk test (2MWT).

EDSS was performed every 3 months.

Median, interquartile ranges and p values were evaluated by Friedman test.

Results

- The mean of follow-up was 19,5 months (13 - 26)

- Outcomes on functional systems were:

Visual functions: at start treatment 0,0 (0.0 - 1.0); at 12 months 0,0 (0.0 - 0.0); at last visit: 0,0 (0.0 - 0.0) p= 0,069

Brainstem functions: at start treatment 0,0 (0.0 - 2.0); at 12 months 0,0 (0.0 - 2.0); at last visit: 0,0 (0.0 - 2.0) p= 0,368

Pyramidal functions: at start treatment 3,0 (2.0 - 3.0); at 12 months 3,0 (2.0 - 3.0); at last visit: 3,0 (2.0 - 3.0) p= 1,000

Cerebellar functions: at start treatment 2,0 (2.0 - 3.0); at 12 months 2,0 (1.0 - 2.0); at last visit: 2,0 (1.0 - 2.0) p= 0,670

Sensory functions: at start treatment 2,0 (2.0 - 3.0); at 12 months 2,0 (2.0 - 3.0); at last visit: 2,0 (2.0 - 3.0) p= 0,867

Bowel and Bladder functions: at start treatment 1,0 (0.0 - 1.0); at 12 months 1,0 (1.0 - 1.0); at last visit: 1,0 (1.0 - 1.0) p= 1,000

Cerebral functions: at start treatment 1,0 (0.0 - 2.0); at 12 months 0,0 (0.0 - 0.0); at last visit: 0,0 (0.0 - 0.0) p= 0,005

Ambulation score: at start treatment 6,0 (2.0 - 7.0); at 12 months 6,0 (3.0 - 7.0); at last visit: 6,0 (5.0 - 8.0) p= 0,323

- The EDSS mean at the start of dalfampridine was 5,61 (4.0 - 6.5), at 12 months 5,5 (3.5 - 7.0) p= 0,339 and at the last visit 5,45 (2.0 - 7.0) p= 0,441.

- There was a negative correlation between sphincter and sensory functions and 2MWT.

Conclusions

We could obtain a relevant effect of dalfampridine on cerebral functions measured over more than a year. Nonetheless, we can not conclude if this outcome is directly related with an effect over cognition or it is related with improvement of fatigue and depression.

EDSS remained stable over more than a year in dalfampridine responsers.

We can not explain why patients who are responsers to dalfampridine had worsening of sphincter and sensory functions at the same time.