Regina Berkovich

Treatment of Acute Relapses in Multiple Sclerosis

SummaryMultiple sclerosis (MS) is a chronic progressive inflammatory demyelinating disease affecting the central nervous system. The most common clinical type of MS tends to follow a relapsing course, affecting the vast majority of patients living with this disease. Relapses are a hallmark of MS, and are often associated with significant functional impairment and decreased quality of life. Although usually followed by a period of remission, residual symptoms after MS relapses may persist and lead to sustained disability. Adequate management of MS relapses is important, as it may help to shorten and lessen the disability associated with their course. Historically, treatment of MS relapse was the first approach (and for a period of time, the only approach) to MS treatment in general. Systemic corticosteroids and adrenocorticotropic hormone (ACTH) have broad regulatory approval and remain the most established and validated treatment options for MS relapse. Therapeutic mechanisms of ACTH were previously associated (perhaps mistakenly) with only corticotropic actions; however, recently the direct anti-inflammatory effects and immunomodulatory activity of ACTH gel acting through melanocortin pathways have been shown. Second-line treatments of steroid-unresponsive MS relapses and a possible algorithm for MS relapse management are also reviewed in this article.

Mechanisms of action of adrenocorticotropic hormone and other melanocortins relevant to the clinical management of patients with multiple sclerosis

The therapeutic benefits of adrenocorticotropic hormone in multiple sclerosis are usually ascribed to its corticotropic actions. Evidence is presented that adrenocorticotropic hormone, approved for multiple sclerosis relapses, acts via corticosteroid-independent melanocortin pathways to engender down-modulating actions on immune-system cells and the cytokines they synthesize. Immune response-dampening effects are also brought about by agent-induced neurotransmitters that inhibit immunocytes. The likelihood that adrenocorticotropic hormone promotes microglial quiescence and counteracts glucocorticoid-mediated bone resorption is discussed.

Effects of dimethyl fumarate on lymphocyte subsets.

OBJECTIVE To evaluate changes in absolute lymphocyte counts, lymphocyte subsets, and infections in patients treated with dimethyl fumarate (DMF) in comparison to the baseline pre-DMF levels. METHODS A retrospective chart review was conducted of 23 MS patients treated with DMF. Absolute lymphocyte counts and lymphocyte subsets were obtained at baseline and after at least 3 months of DMF treatment. Data on infections requiring medical attention were also collected. RESULTS A total of 23 patients were included in this analysis, 11 male (48%), 12 female (52%), with a mean age of 44.5±14.1 years, disease duration of 13.7±8.9 years, and EDSS of 3.5±1.7. The time between baseline and treatment lymphocyte counts was 3.9±1.2 months. Significant reductions in absolute lymphocyte counts by 35% (p<0.0001), CD3(+) by 34% (p<0.0001), CD4(+) by 34% (p<0.0001), CD8(+) by 40% (p<0.0001), and CD19(+) counts by 48% (p=0.0098) were found. Grade 2 lymphopenia occurred in 24% of patients and grade 3 lymphopenia occurred in 1 patient. Infections occurred in 26% of patients, mainly as urinary tract infections (22%) and one fatal case of West Nile encephalitis in a patient with grade 3 lymphopenia, who had been on DMF for 5 months. A detailed summary of this fatal case is provided. CONCLUSION Lymphocyte subsets may help to provide better understanding of immunologic and safety impact of DMF.

Adrenocorticotropic hormone versus methylprednisolone added to interferon β in patients with multiple sclerosis experiencing breakthrough disease: a randomized, rater-blinded trial

Background: The objective of this study was to evaluate monthly intramuscular adrenocorticotropic hormone (ACTH) gel versus intravenous methylprednisolone (IVMP) add-on therapy to interferon β for breakthrough disease in patients with relapsing forms of multiple sclerosis. Methods: This was a prospective, open-label, examiner-blinded, 15-month pilot study evaluating patients with Expanded Disability Status Scale (EDSS) score 3.0–6.5 and at least one clinical relapse or new T2 or gadolinium-enhanced lesion in the previous year. Twenty-three patients were randomized to ACTH (n = 12) or IVMP (n = 11) and completed the study. The primary outcome measure was the cumulative number of relapses. Secondary outcomes included EDSS, Mental Health Inventory (MHI), plasma cytokines, MS Functional Composite (MSFC), Quality-of-Life (MS-QOL) score, bone mineral density (BMD), and new or worsened psychiatric symptoms per month. Brain magnetic resonance imaging was analyzed post hoc. This was a preliminary and small-scale study. Results: Relapse rates differed significantly [ACTH 0.08, 95% confidence interval (CI) 0.01–0.54 versus IVMP 0.80, 95% CI 0.36–1.75; rate ratio, IVMP versus ACTH: 9.56, 95% CI 1.23–74.6; p = 0.03]. ACTH improved (p = 0.03) MHI (slope 0.95 ± 0.38 points/month; p = 0.02 versus slope −0.38 ± 0.43 points/month; p = 0.39). On-study decreases (all p < 0.05) in eight cytokine levels occurred only in the ACTH group. However, on-study EDSS, MSFC, MS-QOL, BMD, and MRI lesion changes were not significant between groups. Psychiatric symptoms per patient were greater with IVMP than ACTH (0.55, 95% CI 0.12–2.6 versus 0; p < 0.0001). Other common adverse events were insomnia and urinary tract infections (IVMP, seven events each) and fatigue or flu symptoms (ACTH, five events each). Conclusions: This study provided class II evidence that ACTH produced better examiner-assessed cumulative rates of relapses per patient than IVMP in the adjunctive treatment of breakthrough disease in multiple sclerosis.

Intravenous valproate inhibits ongoing and evoked activity of dura-sensitive thalamic neurons in rats

Valproate is widely used for migraine treatments, although precise mechanisms of its anticephalgic action are poorly understood. Migraine attacks are thought to occur due to trigemino-vascular system activation, which in turn, stimulates nociceptive transmission in trigemino-thalamo-cortical pathway. The ventroposteromedial (VPM) nucleus of the thalamus is considered to play a prominent role in neurobiology of headaches by serving as the highest subcortical relay for conveying nociceptive information from intra- and extra-cranial structures to the cortex. While it has been demonstrated that valproate can modulate trigemino-vascular nociceptive neurotransmission in the VPM, its effects have been investigated using only intrathalamic ejection of the compound in pentobarbitone sodium anesthetized rats. The objective of our study was to evaluate the effects of intravenously administered valproate on both ongoing firing of the VPM neurons and their activity induced by electrical stimulation of the dura mater. The experiments were performed on rats under nonbarbiturate anesthesia. To define the dose-dependent properties and longevity of the studied effects of valproate, two distinguished dosing regiments were used: bolus (single infusion at a dose of 300 mg/kg) and cumulative (thrice-repeated administration of 100mg/kg performed 30 min apart). Intravenous administration of valproate produced the dose-dependent suppression of both the ongoing activity of the thalamic VPM neurons and their responses to electrical stimulation of the dura mater. This effect was fast-developing (within 5 min) and short-lasting (no longer than 30 min). These data suggest that intravenous administration of valproate could produce a reduction of the thalamo-cortical nociceptive transmission associated with trigemino-vascular activation.

Intravenous dextromethorphan/quinidine inhibits activity of dura-sensitive spinal trigeminal neurons in rats

Migraine is a chronic neurological disorder characterized by episodes of throbbing headaches. Practically all medications currently used in migraine prophylaxis have a number of substantial disadvantages and use limitations. Therefore, the further search for principally new prophylactic antimigraine agents remains an important task. The objective of our study was to evaluate the effects of a fixed combination of dextromethorphan hydrobromide and quinidine sulphate (DM/Q) on activity of the spinal trigeminal neurons in an electrophysiological model of trigemino‐durovascular nociception.

CD4 cell response to interval therapy with natalizumab

Natalizumab treatment alters peripheral CD4 cells counts in multiple sclerosis (MS) patients, providing a way to monitor the pharmacodynamic effects of the drug. The study was undertaken to assess whether CD4 cell counts correlate with different phases of natalizumab treatment of relapsing MS patients, including during a 12‐week planned treatment interruption, and whether that might provide insights on lymphocyte trafficking. Clinical outcomes, MRI data, and CD4 cell counts were assessed at baseline prior to initiating natalizumab, while on regular dosing, at the end of the 12‐week extended dosing interval, and at the time of reinitiation of natalizumab. The 12‐week interruption was well tolerated and not associated with return of MS activity, disability progression, or new or worsened MRI data. Observed significant shifts in CD4 counts – dramatically increasing from the baseline while on treatment and decreasing back to the baseline level off treatment, then rising in a similar manner on natalizumab reinitiation, suggest that these measurements may aid in monitoring modulation of lymphocyte trafficking and cell redistribution.

Teaching NeuroImages: hiccoughs and vomiting in neuromyelitis optica.

A 50-year-old man with a history of recurrent optic neuritis and past thoracic transverse myelitis presented with rapidly progressive quadriparesis, urinary incontinence, dyspnea, dysphagia, dysarthria, intractable hiccoughs, nausea, vomiting, and blurry vision. MRI revealed prominent demyelinating findings at the upper cervical cord and pontomedullary junction …

Clinical and MRI outcomes after stopping or switching disease-modifying therapy in stable MS patients: a case series report

OBJECTIVE To evaluate clinical and MRI outcomes after stopping or switching disease-modifying therapy in patients with stable MS. METHODS A retrospective chart review was conducted of stable MS patients who discontinued or switched their DMT from 2011 to 2015. Clinical and MRI outcomes were obtained at baseline and 1-year follow-up. RESULTS For the DMT discontinuation group, 15 patients were included, with 67% female, 53% Caucasian, mean age of 45.3 ± 12.2 years, disease duration of 9.1 ± 4.3 years, MS type (80% RRMS, 20% SPMS), and EDSS of 3.7 ± 1.6. The average duration of stable MS course was 5.5 ± 3.7 years. Within a mean of 6.4 ± 2.2 months after DMT discontinuation, all 15 patients experienced worsening of MS disease. After re-evaluation of MS treatment options, all 15 patients were restarted on DMT, of which, 6 (40%) restarted on their prior DMT, 4 (26.7%) switched to another DMT due to adverse events on prior DMT, and 5 (33.3%) switched to a more potent DMT due to worsening of MS activity. One year follow-up showed 2 patients (13.3%) who were restarted on their prior DMT experienced a relapse and the remaining 13 patients (86.7%) had no clinical or MRI activities. For the DMT switch group, 23 patients were included, with 65% female, 61% Caucasian, a mean age of 46.9 ± 11.6 years, disease duration of 11.7 ± 5.1 years, MS Type (83% RRMS, 17% SPMS), and EDSS of 3.5 ± 0.9. After switching DMT, 9 (39.1%) patients experienced worsening of clinical or MRI outcomes at the 1-year follow-up. Of the 9 switch failures, the majority (N = 6) were due to switching to dimethyl fumarate. CONCLUSION DMT discontinuation in stable MS patients resulted in worsening of MS disease course for all patients, which improved upon DMT restart or switch. In contrast, 39% of MS stable patients experienced worsening of MS disease course when switched to another DMT, with DMT selection potentially impacting switch outcomes.