Bariatric surgery is gaining acceptance as an efficient treatment modality for adults and adolescents with morbid obesity. The early postbariatric period has the potential to induce an immunomodulatory imbalance due to the development or worsening of nutritional deficiencies, changes in hormonal balance (specifically after sleeve gastrectomy), and a shift in the proinflammatory cytokine profile along with a major change in the gut microbiome and permeability. These changes may induce encephalomyelitic T cell activity, change neural barrier permeability, and induce gut dysbioisis, favoring a proinflammatory metabolic profile. Such changes, in genetically prone individuals or those with additional risk factors, may lead to the development of myelopathy, particularly MS. Key Message: Postbariatric myelopathy is rare but should be considered in bariatric patients with relevant complaints in the postoperative period.

Bariatric surgical procedures are gaining acceptance as an effective and sustainable treatment for patients suffering from morbid obesity and its related complications [1]. The most common procedures currently utilized include the Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), and laparoscopic gastric banding (LAGB). Bariatric procedures induce weight loss by means of 2 basic mechanisms (which vary according to the procedure): mechanical restriction and malabsorption [2]. Additional systemic yet mechanistically important effects are driven by the hormonal and metabolic changes induced by such operations. Bariatric procedures lead to a substantial and relatively rapid weight loss during the first 12–24 months following surgery. In addition to weight loss, these procedures cause a significant reversal of obesity-driven comorbidities such as type 2 diabetes, hypertension, dyslipidemia, and obstructive sleep apnea [3]. Importantly, bariatric procedures initially lead to a consumption of a low-calorie diet inducing rapid weight loss and most patients are required to consume a lifetime replacement of multivitamins aiming at preventing significant nutritional deficiencies [4].

Myelopathies are defined as neurologic deficits related to the spinal cord [5]. Myelopathy can be the result of multiple etiologies, some that may manifest in the postoperative (early and late) phase of bariatric procedures. Specifically, metabolic myelopathies are caused by a specific nutritional deficiency that is crucial for myelin and axon integrity and maintenance. As the postoperative period may be characterized by both nutritional deficiencies as well as a systemic (and specifically adipose tissue) stress response [6] induced by the catabolic weight loss phase, it is reasonable to assume that it may cause some new-onset myelopathies to appear. Here, we describe a morbidly obese teenager who underwent SG and developed neurologic deficits 3 months after surgery. We further review potential mechanistic explanations for the development of postbariatric myelopathy.

A 17-year-old female presented with progressive ascending lower extremity weakness, numbness, and paresthesia starting 4 days earlier. She described paresthesia below the nipple line and a progressive weakness of her lower limbs which meant she could walk independently but unsteadily. She had no history of fever or trauma. Following the onset of these symptoms, she reported urinary incontinence.

Past medical history included morbid obesity since early childhood, documented obstructive sleep apnea, and menorrhagia. The patient had undergone SG 3 months prior to admission. She had been advised to consume the standard postoperative diet, along with vitamin supplementation [7]. Following the operation, she lost 25 kg (i.e., an excess weight loss of 37%). She did not take the vitamin supplements that were prescribed for her before or following the procedure. The patient had no vomiting but reported a very low caloric intake.

The patient was an only child. Both parents suffered from obesity and the mother had undergone bariatric surgery herself. The father passed away from an unknown medical condition. There was no history of any autoimmune disease in their parents or siblings.

Physical examination was unremarkable except for slight weakness in dorsiflexion (4/5) of the lower extremities. Deep tendon reflexes were +2 and symmetric with a negative Babinski sign bilaterally. Sensation was intact except for paresthesia below the nipple line. Gait was slightly unstable but did not fit to any specific neurological pattern. Normal rectal tone was noted and an electromyogram study was normal.

Following a normal cranial CT, a lumbar puncture revealed 6 lymphocytes along with normal glucose and protein levels. Cerebrospinal fluid (CSF) bacterial and viral assays were negative. CSF cytology revealed seemingly normal lymphocytes and monocytes.

The patient had a normal blood count and renal and liver function, and slightly elevated CRP (Table 1). Vitamin B12, vitamin E, and folic acid levels were normal, while low vitamin B1 was noted as well as a very low level of 25-OH vitamin D3. Copper level was normal and toxicologic screening was negative. Anti-MOG and anti-aquaporin-4 antibodies were negative.

Table 1.

Results before and 3 months after the bariatric procedure

Results before and 3 months after the bariatric procedure
Results before and 3 months after the bariatric procedure

Due to the low blood levels of vitamin B1 and her clinical presentation of muscle weakness and suspected neuropathy, vitamin B1 deficiency-related neuropathy was suspected. The patient was treated with an intravenous B1 supplement, vitamin D, and an oral multivitamin supplement. This resulted in a minimal improvement of her clinical symptomatology. At this point, spinal and cranial MRI was performed. Spinal imaging demonstrated a longitudinally extensive myelitis manifesting as swelling of the spinal cord with high-signal intensity on T2-weighted images and strong enhancement between the lower C6 and T1 (Fig. 1). The lesion mainly involved the central gray matter. The brain MRI was normal.

Fig. 1.

a, c First spinal MRI examination showing longitudinal myelitis with increased T2 signal and slight cord expansion at C6 through vitamin D1 levels. b, d Following gadolinium injection, there is central, almost complete enhancement, mainly involving the central cord.

Fig. 1.

a, c First spinal MRI examination showing longitudinal myelitis with increased T2 signal and slight cord expansion at C6 through vitamin D1 levels. b, d Following gadolinium injection, there is central, almost complete enhancement, mainly involving the central cord.

Close modal

A diagnosis of acute transverse myelitis was made, and steroid treatment was initiated. The patient was initially treated with high-dose intravenous steroids and later with oral prednisone, followed by tapering of the dose. She experienced little improvement with this treatment regimen. As a result, she received a series of 6 plasmapheresis cycles that resulted in a significant improvement and was able to walk independently. Three weeks later, her symptoms deteriorated again, and she developed urinary incontinence. Repeated MRI revealed no major changes of the spinal lesion as well as a new lesion within the corpus callosum (not present 3 weeks earlier). A diagnosis of multiple sclerosis (MS) was made. Oligoclonal antibodies in the CSF later returned positive.

We report a case of postbariatric surgery development of a myelopathy, later diagnosed as MS, in a female teenager. This is a rare occurrence and only a handful of cases have been previously described [8]. Neurological complications of bariatric surgery are uncommon and can result from surgical as well as nutritional complications. Most studies reported that only 1.3–16% of patients manifested with neurological complications during the follow-up [9], mainly peripheral neuropathies [10]. Regardless, the postoperative period of bariatric surgery represents a significant nutritional and catabolic stress that may lead to the development of serious myelopathies. We discuss the potential roles of nutritional, hormonal, and immunological effects of surgery in relation to the development of myelopathy.

Pathophysiology and Etiology of Myelopathies and of MS

MS is a chronic inflammatory disease of the central nervous system (CNS) and is the most common cause of nontraumatic neurological disability in young adults [11]. The pathophysiology of MS development is not fully elucidated, but it appears to involve a combination of a genetic susceptibility along with nongenetic triggers such as infections and environmental exposures that, together, lead to an autoimmune dysregulation characterized by recurrent immune attacks on the CNS [12]. The disease appears to develop due to unregulated activation of cell-mediated immune responses that target specific components of the CNS [13].

Acute transverse myelitis has an incidence of 1–4 new cases/1,000,000/year and occurs at all ages, with a typical bimodal peak in the second and fourth decades of life, with no difference between the genders, no seasonal variations, and no specific predisposing familial history [14]. Alongside infectious and inflammatory etiologies of this condition, nutritional deficiencies are a significant component of the differential diagnosis. Subacute combined degeneration has traditionally been used to describe the myeloneuropathy associated with vitamin B12 deficiency. This myelopathy typically presents with physical findings suggestive of lesions within the dorsal column, corticospinal tract, or peripheral nerves. Copper deficiency can present with clinical and imaging findings similar to those of transverse myelitis. The most common manifestation of acquired copper deficiency is myelopathy or myeloneuropathy that resembles the subacute combined degeneration seen with vitamin B12 deficiency. Hematological manifestation of acquired copper deficiency includes anemia and neutropenia. Of the usual causes of acquired copper deficiency, the most common is a prior history of gastric surgery. Vitamin E deficiency has been shown to present with similar clinical findings, with a specific predilection to include the cerebellar pathways. Neurologic manifestations of vitamin E deficiency include peripheral neuropathies as well as a progressive spinocerebellar syndrome with corticospinal tract dysfunction.

Acute transverse myelitis can be the initial presentation of MS [15] (as in the case presented here), but MS typically presents with a partial myelitis, with either motor or sensory symptoms present, while bowel and bladder function is usually not compromised at this stage. The description of longitudinal extensive myelitis on presentation is more typical of the neuromyelitis optica spectrum. Our patient did not meet the diagnostic criteria for this condition.

Postbariatric Nutritional Deficiencies

Several reports have shown that morbidly obese individuals in general, and particularly bariatric surgery candidates, tend to have significant nutritional deficiencies [16]. These range from iron deficiency to clinically significant vitamin D depletion and low folic acid levels. Such observations have been observed in adults as well as in obese teenagers like our patient. It is well established that failure to replenish vitamin and mineral stores prior to the bariatric procedure usually results in substantial nutritional deficiencies following the operation [17]. Despite the fact that multivitamin supplementation is a critical component of the postoperative management of patients, low compliance along with objective difficulties of swallowing without vomiting, specifically in the early postoperative period, are common among these patients.

One of the suspected environmental factors is a higher latitude, as the prevalence and incidence of the disease is greater in northern areas such as in Scandinavia. Higher latitude correlates mainly with lower sunlight exposure, and it has been demonstrated that the risk of developing MS is inversely correlated with the amount of sunlight exposure [18]. The main metabolic impact of sunlight exposure in this context is on the synthesis of vitamin D. The specific role of vitamin D (but not sunlight UV exposure per se) in the pathophysiology of MS is supported by studies showing that a higher maternal dietary intake of the vitamin during pregnancy [19] and in young adults generally [20], seems to be protective against MS developing.

The mechanisms of involvement of vitamin D in MS development appear to be immunomodulatory. They involve effects on multiple subclasses of T and B lymphocytes. In vitro studies using 1–25 vitamin D show that it induces enhanced production of interleukin (IL)-10 by B lymphocytes [21], which is relevant in this context as there seems to be a link between B cell production of this IL and protection from autoimmune nervous system involvement [22, 23]. Similarly, in vitro vitamin D induces an interference in plasma cell IgG secretion as well as an inhibition of development of post-switched memory B cells [24]. This may be relevant to the development and/or progression of MS, as high-affinity antibodies that may have switched class are postulated to be major drivers of both the development and progression of the disease. Indeed, our patient demonstrated significantly low levels of vitamin D, which is commonly observed in obese bariatric surgery candidates [16] prior to and following surgery [25].

Vit B1 deficiency has been demonstrated in 5–30% of bariatric surgery candidates and in up to 30% within 5 years of bariatric procedures [26, 27]. This vitamin is not synthesized endogenously in humans and maintenance of its normal levels depends on exogenous consumption. Low levels will typically present as peripheral neuropathy but can progress to full-blown Wernicke’s encephalopathy. Our patient had low vitamin B1 levels upon presentation, but she responded minimally to aggressive B1 supplementation so her initial presentation with transverse myelitis was not due to this deficiency. The typical time frame for the clinical manifestations of vitamin B1 deficiency to develop is up to 12 months, longer than that of our patient [28].

Vitamin B12 deficiency common develops after SG due to the loss of a significant proportion of the stomach [17, 29]. Vitamin B12 deficiency has been known for decades to be commonly present in patients with new-onset MS and is postulated to impact the development and clinical course of the disease. Whether vitamin B12 deficiency is indeed associated with MS and its exact potential causative role in disease development are still controversial in the literature [30]. Similarly, vitamin A deficiency is often encountered following SG [31]. An inverse association has been demonstrated between serum retinol levels and simultaneous and subsequent MRI outcomes, but not with clinical findings, in relapsing remitting MS [32]. Iron deficiency is very common after SG [25]. Iron supplementation is recommended postoperatively to all patients who undergo SG, but this may prove particularly tricky in the context of MS. Iron deposition in the brain has been suggested to contribute to the development of MS [33] but there is also a subgroup of patients with MS who improve significantly in response to iron supplementation [34]. These conflicting observations regarding the impact of iron on MS emphasize the broad spectrum of this disease and the necessity of an individualized nutritional approach. These observations suggest that vitamins, trace elements, and their metabolites may impact the clinical course and possibly the disease development in MS patients. Acquired myelopathy following bariatric procedures has been described due to copper deficiency. This complication tends to present years after the operation and is probably due to low copper consumption and absorption. As the absorption of copper takes place in the stomach and proximal duodenum [35], it is not surprising that copper deficiency may develop following bariatric procedures [36]. The time course of the development of this deficiency was less relevant for our patient who had a normal plasma copper concentration.

Postbariatric Cytokine and Chemokine Dynamics

Obesity is associated with a low-grade inflammatory chronic state, mainly due to cytokine secretion from various lipid deposits [37]. This chronic subclinical inflammation is acutely exacerbated following bariatric procedures due to accelerated adipose tissue breakdown by lipolysis, typical of the rapid weight loss phase during the initial postoperative period [38]. The anatomical disruption of neuronal and hormonal pathways associated with bariatric procedures can lead to an activation of inflammatory signaling pathways and lead to accelerated cytokine production. For example, it been demonstrated that IL-8 concentrations tend to increase in the early postoperative phase of bariatric procedures. In patients with relapsing MS, IL-8 was found to be higher than in healthy controls. Interestingly, levels of IL-8 tended to be much higher in the CSF than in the serum in such patients [39]. IL-6 levels have been shown to increase in the early postbariatric surgery period [40] and to remain so for at least 6 months, after which they decline. Studies in vivo and in vitro have found that IL-6 is crucially involved in regulating the immune response in MS and may have a significant impact on the development and progression of the disease [41]. Specifically, overproduction of IL-6 has been shown to induce autoimmune diseases such as MS as well as rheumatoid arthritis (RA), in which T helper (Th)17 cells are considered the primary drivers of pathology [42]. Th17 cells are one of the producers of IL-17, and high IL-17 gene expression levels have been shown in mononuclear cells derived from the blood and CSF of MS patients [43] and the CD41 and CD81 T cells derived from MS lesions [44]. Th17 cells are able to cross and also damage the integrity of the blood-brain barrier (BBB), thus facilitating the infiltration of blood-derived proinflammatory cells into the nervous system. As such cells secrete IL-17A and many other cytokines, they may locally induce immune responses by altering the functionality multiple neuronal cells and networks, with the potential to cause axonal damage, demyelination, and neuronal apoptosis [45]. From the perspective of autoimmunity, there are several examples in the literature of other autoimmune conditions developing within less than a year of bariatric procedures, although the mechanisms involved are unclear [46]. Taken together, these observations may hint that the acute weight loss early in the postoperative period may, in some patients, create an immune imbalance that is involved in the development of autoimmune lesions of the nervous system.

Postbariatric Hormonal Changes

Weight loss, particularly bariatric procedures, has a profound impact on circulating concentrations of the multiple hormones involved in the metabolism. A specific hormone relevant for this discussion is ghrelin. Ghrelin is produced by specialized endocrine cells of the stomach [47] and its concentration increases before meals to centrally stimulate food intake. Ghrelin concentration typically increases after diet-induced weight loss [48], but it is significantly reduced after bariatric procedures that excise substantial stomach mass, e.g., SG [49, 50]. In the rodent model of MS (experimental autoimmune encephalomyelitis, EAE), ghrelin administration leads to a reduction of proinflammatory cytokines (e.g., IL-6 and TNF-α) and also of cellular infiltrates in the spinal cord [51]. Ghrelin has been shown to reduce the presence and activation of Th1 and Th17 cells in the nervous system and to induce regulatory T cells in this model [52]. Ghrelin treatment in rodent models of traumatic brain injury has been shown to prevent cortical volume loss and neurodegeneration. In the same model, ghrelin improved posttraumatic motor deficits [53]. In other rodent models (diabetic rats), ghrelin has been shown to ameliorate astrocytic activation and reduce the expression of the abovementioned proinflammatory cytokines [54]. The mechanisms by which ghrelin induces its effects on the nervous system are still unclear, but the combination of the antiapoptotic and immune cell inflammatory modulatory effects may be advantageous in certain pathological conditions. Indeed, the anti-inflammatory role of ghrelin in the CNS is so profound that it has been proposed as a potential therapeutic intervention for MS [55].

A second hormone that is significantly reduced following dieting or surgically induced weight loss is leptin. Leptin is an adipocyte-derived hormone whose major role is to signal the size and availability of fat deposits (energy excess vs. shortage) to homeostatic brain centers and thus regulate energy expenditure [56]. Above and beyond its effects on energy regulation, leptin has been shown to impact immune function at several levels [57]. It has been hypothesized that a potential link exists between energy and nutritional metabolism and the pathogenesis of MS. Indeed, epidemiological data show that obesity, a high leptin state, increases the risk of developing MS in young females [58]. Indeed, elevated leptin levels are associated with chronic inflammatory conditions and autoimmune diseases (such as type 1 diabetes and lupus) in humans [59, 60]. Supporting this hypothesis are the findings suggesting that proinflammatory mediators such as leptin maintain microenvironmental conditions that promote loss of immune self-tolerance. Leptin has also been shown to promote proinflammatory immune responses and inhibit the proliferation of anti-inflammatory regulatory T cells (T-regs) [61]. Moreover, leptin can affect the proliferation and the responsiveness of T-regs, a key subpopulation of T cells that are actively involved in the modulation of peripheral tolerance [62]. As mentioned above, orexigenic peptides and molecules such as neuropeptide Y and ghrelin oppose the effects of leptin, in homeostatic hypothalamic nuclei in the context of caloric intake, and also on the peripheral immune response, and in diseases such as MS [63]. Studies on the natural history of MS have shown that >60% of individuals exhibit reductions in body weight before MS onset, suggesting that the intrathecal balance between orexogenic factors (like ghrelin) and anorexogenic factors (like leptin) may be shifted in the early phases of the disease [61]. While bariatric procedures cause weight loss and thus reduce leptin levels, at least in the early phases postoperatively, patients still have higher than normal leptin levels. On the other hand, SG causes a drastic reduction in ghrelin and may thus shift the orexogenic/anorexogenic balance of the CNS to a relatively greater proinflammatory effect of leptin. Whether the acute reduction in ghrelin following SG plays a mechanistic role in the development of MS in predisposed individuals remains to be tested.

Gut Microbiota and the Development of MS

Several observations indicate that patients with MS display bacterial dysbiosis characterized by a reduced diversity and mass of the colonic microbiome [64]. Perturbations of the intestinal microbiome may play a role in the pathogenesis of inflammatory diseases such as MS. Specifically, using the EAE model, it has been shown that microbiota are prominent drivers of the triggering of autoimmune demyelination [65]. In addition, the gut microbiome may modulate the systemic and local host immune system, as well as modify the functionality and integrity of natural membranes and barriers. In the rodent model, dysbiosis induces the expression of complement C3 and the production of the anaphylatoxin C3a, while downregulating the expression of the Foxp3 gene and anergy-related E3 ubiquitin ligase genes [66]. Thus, microbiome dysbiosis may be able to trigger the development of encephalitis-promoting T cells and induce the development of EAE.

Data from rodent models and from humans indicates that gut microbiota composition is modified following bariatric surgery, suggesting that weight reduction may have an impact on gut microbiota profiles [67]. Dietary content [66, 68] and weight loss per se [8] have been shown to alter the clinical course of EAE in rodents and of MS in humans. Importantly, the RYGB procedure produces greater and more favorable changes in microbiota diversity and functional capacity than SG [69]. SG (the bariatric procedure that our patient underwent), on the other hand, induces an increase in the permeability of the colon, regardless of the small dynamic changes in microbiota [70]. While the changes of the microbiota profile induced by bariatric procedures and diet-induced weight loss have been viewed favorably in the context of weight dynamics (changing the microbiome to that more reminiscent of a lean individual), the modest change induced by SG and its impact on gut permeability may potentially have an adverse effect that alters immune tolerance and promotes an increase in specific T cell populations that can influence the development of MS, as observed in the EAE model.

An interesting point arises with regard to the impact of a very low-calorie diet (VLCD) in cases of established MS. There are several ongoing clinical trials testing fast-mimicking and ketogenic diets in patients with MS [71]. These stem from observations regarding the positive effects of such diets in the rodent model of autoimmune encephalomyelitis [72]. It is postulated that the mechanism by which a dietary intervention may affect the clinical course of MS is related to the effects of the type and concentrations of specific nutrients that can influence the generation and functionality of lymphocytes, and thereby modulate autoimmunity and immunosenescence [73]. Similarly, caloric density and specific components of the diet may impact microbiota composition and thus alter the course of MS via the effects on relevant lymphocyte populations.

Bariatric surgery is gaining acceptance as an efficient treatment modality for adolescents with morbid obesity. The early postbariatric period has the potential to induce an immunomodulatory imbalance due to the development or worsening of nutritional deficiencies, changes in the hormonal balance (specifically following SG), and a shift in the proinflammatory cytokine profile, along with a major change in gut microbiome and permeability (Fig. 2). Such changes, in genetically prone individuals or those with additional risk factors, may lead to the development of a myelopathy, in general, and MS, in particular. These postbariatric complications are rare but should be considered in patients with relevant complaints in the postoperative period.

Fig. 2.

The multiple elements related to bariatric surgery that may be involved in the development of myelopathies. Patients with a specific genetic predisposition who are obese are exposed to additional potential elements related to bariatric procedures that may induce the development of myelopathy and multiple sclerosis.

Fig. 2.

The multiple elements related to bariatric surgery that may be involved in the development of myelopathies. Patients with a specific genetic predisposition who are obese are exposed to additional potential elements related to bariatric procedures that may induce the development of myelopathy and multiple sclerosis.

Close modal

Written informed consent was obtained from the patient (now an adult) for publication of this case report and any accompanying MRI images.

There were no conflicts of interest. R.W. serves a consultant for Medtronic, Novo Nordisk, and Eli Lilly and received grants from the Israel Ministry of Science and Israel Ministry of Health (neither related to the topic in this paper). P.M.R. received a grant from the Israel Society of Pediatrics and the Israel Society of Pediatric Gastroenterology (neither related to the topic in this paper).

There was no funding.

S.A., R.M.-R., and R.W. wrote the manuscript and took part in clinical care. A.I., M.M.-S., T.B.-P., S.R., A.E., V.G., and S.H. commented on the text, added insights, and took part in the clinical care. All authors reviewed and approved the final version.

1.
Wolfe
BM
,
Kvach
E
,
Eckel
RH
.
Treatment of Obesity: Weight Loss and Bariatric Surgery
.
Circ Res
.
2016
May
;
118
(
11
):
1844
55
.
[PubMed]
0009-7330
2.
le Roux
CW
,
Heneghan
HM
.
Bariatric Surgery for Obesity
.
Med Clin North Am
.
2018
Jan
;
102
(
1
):
165
82
.
[PubMed]
0025-7125
3.
Puzziferri
N
,
Roshek
TB
 3rd
,
Mayo
HG
,
Gallagher
R
,
Belle
SH
,
Livingston
EH
.
Long-term follow-up after bariatric surgery: a systematic review
.
JAMA
.
2014
Sep
;
312
(
9
):
934
42
.
[PubMed]
0098-7484
4.
Salameh
BS
,
Khoukaz
MT
,
Bell
RL
,
Bell
RL
.
Metabolic and nutritional changes after bariatric surgery
.
Expert Rev Gastroenterol Hepatol
.
2010
Apr
;
4
(
2
):
217
23
.
[PubMed]
1747-4124
5.
Hedera
P
.
Hereditary and metabolic myelopathies
.
Handb Clin Neurol
.
2016
;
136
:
769
85
.
[PubMed]
0072-9752
6.
Kratz
M
,
Hagman
DK
,
Kuzma
JN
,
Foster-Schubert
KE
,
Chan
CP
,
Stewart
S
, et al
Improvements in glycemic control after gastric bypass occur despite persistent adipose tissue inflammation
.
Obesity (Silver Spring)
.
2016
Jul
;
24
(
7
):
1438
45
.
[PubMed]
1930-7381
7.
Mechanick
JI
,
Youdim
A
,
Jones
DB
,
Garvey
WT
,
Hurley
DL
,
McMahon
MM
, et al;
American Society for Metabolic & Bariatric Surgery
.
Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient—2013 update: cosponsored by American Association of Clinical Endocrinologists, The Obesity Society, and American Society for Metabolic & Bariatric Surgery
.
Obesity (Silver Spring)
.
2013
Mar
;
21
Suppl 1
:
S1
27
.
[PubMed]
1930-7381
8.
Alanazy
MH
,
Alomar
MA
,
Aljafen
BN
,
Muayqil
TA
.
Multiple sclerosis and myasthenia gravis following severe weight loss
.
Neurosciences (Riyadh)
.
2018
Apr
;
23
(
2
):
158
61
.
[PubMed]
1319-6138
9.
Koffman
BM
,
Greenfield
LJ
,
Ali
II
,
Pirzada
NA
.
Neurologic complications after surgery for obesity
.
Muscle Nerve
.
2006
Feb
;
33
(
2
):
166
76
.
[PubMed]
0148-639X
10.
Thaisetthawatkul
P
,
Collazo-Clavell
ML
,
Sarr
MG
,
Norell
JE
,
Dyck
PJ
.
A controlled study of peripheral neuropathy after bariatric surgery
.
Neurology
.
2004
Oct
;
63
(
8
):
1462
70
.
[PubMed]
0028-3878
11.
Noseworthy
JH
,
Lucchinetti
C
,
Rodriguez
M
,
Weinshenker
BG
.
Multiple sclerosis
.
N Engl J Med
.
2000
Sep
;
343
(
13
):
938
52
.
[PubMed]
0028-4793
12.
Dendrou
CA
,
Fugger
L
,
Friese
MA
.
Immunopathology of multiple sclerosis
.
Nat Rev Immunol
.
2015
Sep
;
15
(
9
):
545
58
.
[PubMed]
1474-1733
13.
Correale
J
,
Gaitán
MI
,
Ysrraelit
MC
,
Fiol
MP
.
Progressive multiple sclerosis: from pathogenic mechanisms to treatment
.
Brain
.
2017
Mar
;
140
(
3
):
527
46
.
[PubMed]
1460-2156
14.
MJ
.
Acute transverse myelitis: a practical reappraisal
.
Autoimmun Rev
.
2009
Dec
;
9
(
2
):
128
31
.
[PubMed]
1568-9972
15.
Fisniku
LK
,
Brex
PA
,
Altmann
DR
,
Miszkiel
KA
,
Benton
CE
,
Lanyon
R
, et al
Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis
.
Brain
.
2008
Mar
;
131
(
Pt 3
):
808
17
.
[PubMed]
0006-8950
16.
Ben-Porat
T
,
Elazary
R
,
Yuval
JB
,
Wieder
A
,
Khalaileh
A
,
Weiss
R
.
Nutritional deficiencies after sleeve gastrectomy: can they be predicted preoperatively?
Surg Obes Relat Dis
.
2015
Sep-Oct
;
11
(
5
):
1029
36
.
[PubMed]
1550-7289
17.
Damms-Machado
A
,
Friedrich
A
,
Kramer
KM
,
Stingel
K
,
Meile
T
,
Küper
MA
, et al
Pre- and postoperative nutritional deficiencies in obese patients undergoing laparoscopic sleeve gastrectomy
.
Obes Surg
.
2012
Jun
;
22
(
6
):
881
9
.
[PubMed]
0960-8923
18.
Lucas
RM
,
Byrne
SN
,
Correale
J
,
Ilschner
S
,
Hart
PH
.
Ultraviolet radiation, vitamin D and multiple sclerosis
.
Neurodegener Dis Manag
.
2015
Oct
;
5
(
5
):
413
24
.
[PubMed]
1758-2024
19.
Mirzaei
F
,
Michels
KB
,
Munger
K
,
O’Reilly
E
,
Chitnis
T
,
Forman
MR
, et al
Gestational vitamin D and the risk of multiple sclerosis in offspring
.
Ann Neurol
.
2011
Jul
;
70
(
1
):
30
40
.
[PubMed]
0364-5134
20.
Munger
KL
,
Zhang
SM
,
O’Reilly
E
,
Hernán
MA
,
Olek
MJ
,
Willett
WC
, et al
Vitamin D intake and incidence of multiple sclerosis
.
Neurology
.
2004
Jan
;
62
(
1
):
60
5
.
[PubMed]
0028-3878
21.
Heine
G
,
Niesner
U
,
Chang
HD
,
Steinmeyer
A
,
Zügel
U
,
Zuberbier
T
, et al
1,25-dihydroxyvitamin D(3) promotes IL-10 production in human B cells
.
Eur J Immunol
.
2008
Aug
;
38
(
8
):
2210
8
.
[PubMed]
0014-2980
22.
Duddy
M
,
Niino
M
,
Adatia
F
,
Hebert
S
,
Freedman
M
,
Atkins
H
, et al
Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis
.
J Immunol
.
2007
May
;
178
(
10
):
6092
9
.
[PubMed]
0022-1767
23.
Duddy
ME
,
Alter
A
,
Bar-Or
A
.
Distinct profiles of human B cell effector cytokines: a role in immune regulation?
J Immunol
.
2004
Mar
;
172
(
6
):
3422
7
.
[PubMed]
0022-1767
24.
Chen
S
,
Sims
GP
,
Chen
XX
,
Gu
YY
,
Chen
S
,
Lipsky
PE
.
Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation
.
J Immunol
.
2007
Aug
;
179
(
3
):
1634
47
.
[PubMed]
0022-1767
25.
Ben-Porat
T
,
Elazary
R
,
Goldenshluger
A
,
Sherf Dagan
S
,
Mintz
Y
,
Weiss
R
.
Nutritional deficiencies four years after laparoscopic sleeve gastrectomy-are supplements required for a lifetime?
Surg Obes Relat Dis
.
2017
Jul
;
13
(
7
):
1138
44
.
[PubMed]
1550-7289
26.
van Rutte
PW
,
Aarts
EO
,
Smulders
JF
,
Nienhuijs
SW
.
Nutrient deficiencies before and after sleeve gastrectomy
.
Obes Surg
.
2014
Oct
;
24
(
10
):
1639
46
.
[PubMed]
0960-8923
27.
Saif
T
,
Strain
GW
,
Dakin
G
,
Gagner
M
,
Costa
R
,
Pomp
A
.
Evaluation of nutrient status after laparoscopic sleeve gastrectomy 1, 3, and 5 years after surgery
.
Surg Obes Relat Dis
.
2012
Sep-Oct
;
8
(
5
):
542
7
.
[PubMed]
1550-7289
28.
Punchai
S
,
Hanipah
ZN
,
Meister
KM
,
Schauer
PR
,
Brethauer
SA
,
Aminian
A
.
Neurologic Manifestations of Vitamin B Deficiency after Bariatric Surgery
.
Obes Surg
.
2017
Aug
;
27
(
8
):
2079
82
.
[PubMed]
0960-8923
29.
Majumder
S
,
Soriano
J
,
Louie Cruz
A
,
Dasanu
CA
.
Vitamin B12 deficiency in patients undergoing bariatric surgery: preventive strategies and key recommendations
.
Surg Obes Relat Dis
.
2013
Nov-Dec
;
9
(
6
):
1013
9
.
[PubMed]
1550-7289
30.
Najafi
MR
,
Shaygannajad
V
,
Mirpourian
M
,
Gholamrezaei
A
.
Vitamin B(12) Deficiency and Multiple Sclerosis; Is there Any Association?
Int J Prev Med
.
2012
Apr
;
3
(
4
):
286
9
.
[PubMed]
2008-8213
31.
Jalilvand
A
,
Blaszczak
A
,
Needleman
B
,
Hsueh
W
,
Noria
S
,
Vitamin
A
.
Vitamin A Deficiency in Patients Undergoing Sleeve Gastrectomy and Gastric Bypass: A 2-Year, Single-Center Review
.
J Laparoendosc Adv Surg Tech A
.
2020
Jan
;
30
(
1
):
20
30
.
[PubMed]
1092-6429
32.
Løken-Amsrud
KI
,
Myhr
KM
,
Bakke
SJ
,
Beiske
AG
,
Bjerve
KS
,
Bjørnarå
BT
, et al
Retinol levels are associated with magnetic resonance imaging outcomes in multiple sclerosis
.
Mult Scler
.
2013
Apr
;
19
(
4
):
451
7
.
[PubMed]
1352-4585
33.
Zamboni
P
.
The big idea: iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis
.
J R Soc Med
.
2006
Nov
;
99
(
11
):
589
93
.
[PubMed]
0141-0768
34.
van Rensburg
SJ
,
Kotze
MJ
,
Hon
D
,
Haug
P
,
Kuyler
J
,
Hendricks
M
, et al
Iron and the folate-vitamin B12-methylation pathway in multiple sclerosis
.
Metab Brain Dis
.
2006
Sep
;
21
(
2-3
):
121
37
.
[PubMed]
0885-7490
35.
Myint
ZW
,
Oo
TH
,
Thein
KZ
,
Tun
AM
,
Saeed
H
.
Copper deficiency anemia: review article
.
Ann Hematol
.
2018
Sep
;
97
(
9
):
1527
34
.
[PubMed]
0939-5555
36.
Griffith
DP
,
Liff
DA
,
Ziegler
TR
,
Esper
GJ
,
Winton
EF
.
Acquired copper deficiency: a potentially serious and preventable complication following gastric bypass surgery
.
Obesity (Silver Spring)
.
2009
Apr
;
17
(
4
):
827
31
.
[PubMed]
1930-7381
37.
Wensveen
FM
,
Valentić
S
,
Šestan
M
,
Turk Wensveen
T
,
Polić
B
.
The “Big Bang” in obese fat: events initiating obesity-induced adipose tissue inflammation
.
Eur J Immunol
.
2015
Sep
;
45
(
9
):
2446
56
.
[PubMed]
0014-2980
38.
Federico
A
,
D’Aiuto
E
,
Borriello
F
,
Barra
G
,
Gravina
AG
,
Romano
M
, et al
Fat: a matter of disturbance for the immune system
.
World J Gastroenterol
.
2010
Oct
;
16
(
38
):
4762
72
.
[PubMed]
1007-9327
39.
Sisay
S
,
Lopez-Lozano
L
,
Mickunas
M
,
Quiroga-Fernández
A
,
Palace
J
,
Warnes
G
, et al
Untreated relapsing remitting multiple sclerosis patients show antibody production against latent Epstein Barr Virus (EBV) antigens mainly in the periphery and innate immune IL-8 responses preferentially in the CNS
.
J Neuroimmunol
.
2017
May
;
306
:
40
5
.
[PubMed]
0165-5728
40.
Lindegaard
KK
,
Jorgensen
NB
,
Just
R
,
Heegaard
PM
,
Madsbad
S
.
Effects of Roux-en-Y gastric bypass on fasting and postprandial inflammation-related parameters in obese subjects with normal glucose tolerance and in obese subjects with type 2 diabetes
.
Diabetol Metab Syndr
.
2015
Feb
;
7
(
1
):
12
.
[PubMed]
1758-5996
41.
Janssens
K
,
Slaets
H
,
Hellings
N
.
Immunomodulatory properties of the IL-6 cytokine family in multiple sclerosis
.
Ann N Y Acad Sci
.
2015
Sep
;
1351
(
1
):
52
60
.
[PubMed]
0077-8923
42.
Kimura
A
,
Kishimoto
T
.
IL-6: regulator of Treg/Th17 balance
.
Eur J Immunol
.
2010
Jul
;
40
(
7
):
1830
5
.
[PubMed]
0014-2980
43.
Matusevicius
D
,
Kivisäkk
P
,
He
B
,
Kostulas
N
,
Ozenci
V
,
Fredrikson
S
, et al
Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis
.
Mult Scler
.
1999
Apr
;
5
(
2
):
101
4
.
[PubMed]
1352-4585
44.
Tzartos
JS
,
Friese
MA
,
Craner
MJ
,
Palace
J
,
Newcombe
J
,
Esiri
MM
, et al
Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis
.
Am J Pathol
.
2008
Jan
;
172
(
1
):
146
55
.
[PubMed]
0002-9440
45.
Wang
X
,
Ma
C
,
Wu
J
,
Zhu
J
.
Roles of T helper 17 cells and interleukin-17 in neuroautoimmune diseases with emphasis on multiple sclerosis and Guillain-Barré syndrome as well as their animal models
.
J Neurosci Res
.
2013
Jul
;
91
(
7
):
871
81
.
[PubMed]
0360-4012
46.
Cañas
CA
,
Echeverri
AF
,
Ospina
FE
,
Suso
JP
,
Agualimpia
A
,
Echeverri
A
, et al
Is Bariatric Surgery a Trigger Factor for Systemic Autoimmune Diseases?
J Clin Rheumatol
.
2016
Mar
;
22
(
2
):
89
91
.
[PubMed]
1076-1608
47.
Kojima
M
,
Hosoda
H
,
Date
Y
,
Nakazato
M
,
Matsuo
H
,
Kangawa
K
.
Ghrelin is a growth-hormone-releasing acylated peptide from stomach
.
Nature
.
1999
Dec
;
402
(
6762
):
656
60
.
[PubMed]
0028-0836
48.
Zigman
JM
,
Bouret
SG
,
Andrews
ZB
.
Obesity Impairs the Action of the Neuroendocrine Ghrelin System
.
Trends Endocrinol Metab
.
2016
Jan
;
27
(
1
):
54
63
.
[PubMed]
1043-2760
49.
Kalinowski
P
,
Paluszkiewicz
R
,
Wróblewski
T
,
Remiszewski
P
,
Grodzicki
M
,
Bartoszewicz
Z
, et al
Ghrelin, leptin, and glycemic control after sleeve gastrectomy versus Roux-en-Y gastric bypass-results of a randomized clinical trial
.
Surg Obes Relat Dis
.
2017
Feb
;
13
(
2
):
181
8
.
[PubMed]
1550-7289
50.
Anderson
B
,
Switzer
NJ
,
Almamar
A
,
Shi
X
,
Birch
DW
,
Karmali
S
.
The impact of laparoscopic sleeve gastrectomy on plasma ghrelin levels: a systematic review
.
Obes Surg
.
2013
Sep
;
23
(
9
):
1476
80
.
[PubMed]
0960-8923
51.
Theil
MM
,
Miyake
S
,
Mizuno
M
,
Tomi
C
,
Croxford
JL
,
Hosoda
H
, et al
Suppression of experimental autoimmune encephalomyelitis by ghrelin
.
J Immunol
.
2009
Aug
;
183
(
4
):
2859
66
.
[PubMed]
0022-1767
52.
Souza-Moreira
L
,
Delgado-Maroto
V
,
Morell
M
,
O’Valle
F
,
Del Moral
RG
,
Gonzalez-Rey
E
.
Therapeutic effect of ghrelin in experimental autoimmune encephalomyelitis by inhibiting antigen-specific Th1/Th17 responses and inducing regulatory T cells
.
Brain Behav Immun
.
2013
May
;
30
:
54
60
.
[PubMed]
0889-1591
53.
Lopez
NE
,
Lindsay
G
,
Karina
LR
,
Mary
HA
,
Putnam
J
,
Eliceiri
B
, et al
Ghrelin decreases motor deficits after traumatic brain injury
.
J Surg Res
.
2014
Mar
;
187
(
1
):
230
6
.
[PubMed]
0022-4804
54.
Zhao
Y
,
Shen
Z
,
Zhang
D
,
Luo
H
,
Chen
J
,
Sun
Y
, et al
Ghrelin ameliorates nerve growth factor Dysmetabolism and inflammation in STZ-induced diabetic rats
.
Metab Brain Dis
.
2017
Jun
;
32
(
3
):
903
12
.
[PubMed]
0885-7490
55.
de Candia
P
,
Matarese
G.
Leptin and ghrelin: Sewing metabolism onto neurodegeneration. Neuropharmacology.
2018
;136(Pt B):307-16.
56.
Ahima
RS
,
Flier
JS
.
Adipose tissue as an endocrine organ
.
Trends Endocrinol Metab
.
2000
Oct
;
11
(
8
):
327
32
.
[PubMed]
1043-2760
57.
La Cava
A
,
Matarese
G
.
The weight of leptin in immunity
.
Nat Rev Immunol
.
2004
May
;
4
(
5
):
371
9
.
[PubMed]
1474-1733
58.
Munger
KL
,
Chitnis
T
,
Ascherio
A
.
Body size and risk of MS in two cohorts of US women
.
Neurology
.
2009
Nov
;
73
(
19
):
1543
50
.
[PubMed]
0028-3878
59.
Härle
P
,
Pongratz
G
,
Weidler
C
,
Büttner
R
,
Schölmerich
J
,
Straub
RH
.
Possible role of leptin in hypoandrogenicity in patients with systemic lupus erythematosus and rheumatoid arthritis
.
Ann Rheum Dis
.
2004
Jul
;
63
(
7
):
809
16
.
[PubMed]
0003-4967
60.
Iacobellis
G
,
Diaz
S
,
Mendez
A
,
Goldberg
R
.
Increased epicardial fat and plasma leptin in type 1 diabetes independently of obesity
.
Nutr Metab Cardiovasc Dis
.
2014
Jul
;
24
(
7
):
725
9
.
[PubMed]
0939-4753
61.
Matarese
G
,
Carrieri
PB
,
Montella
S
,
De Rosa
V
,
La Cava
A
.
Leptin as a metabolic link to multiple sclerosis
.
Nat Rev Neurol
.
2010
Aug
;
6
(
8
):
455
61
.
[PubMed]
1759-4758
62.
Taleb
S
,
Herbin
O
,
Ait-Oufella
H
,
Verreth
W
,
Gourdy
P
,
Barateau
V
, et al
Defective leptin/leptin receptor signaling improves regulatory T cell immune response and protects mice from atherosclerosis
.
Arterioscler Thromb Vasc Biol
.
2007
Dec
;
27
(
12
):
2691
8
.
[PubMed]
1079-5642
63.
Bedoui
S
,
Miyake
S
,
Lin
Y
,
Miyamoto
K
,
Oki
S
,
Kawamura
N
, et al
Neuropeptide Y (NPY) suppresses experimental autoimmune encephalomyelitis: NPY1 receptor-specific inhibition of autoreactive Th1 responses in vivo
.
J Immunol
.
2003
Oct
;
171
(
7
):
3451
8
.
[PubMed]
0022-1767
64.
Swidsinski
A
,
Dörffel
Y
,
Loening-Baucke
V
,
Gille
C
,
Göktas
Ö
,
Reißhauer
A
, et al
Reduced Mass and Diversity of the Colonic Microbiome in Patients with Multiple Sclerosis and Their Improvement with Ketogenic Diet
.
Front Microbiol
.
2017
Jun
;
8
:
1141
.
[PubMed]
1664-302X
65.
Calvo-Barreiro
L
,
Eixarch
H
,
Montalban
X
,
Espejo
C
.
Combined therapies to treat complex diseases: the role of the gut microbiota in multiple sclerosis
.
Autoimmun Rev
.
2018
Feb
;
17
(
2
):
165
74
.
[PubMed]
1568-9972
66.
Yadav
SK
,
Boppana
S
,
Ito
N
,
Mindur
JE
,
Mathay
MT
,
Patel
A
, et al
Gut dysbiosis breaks immunological tolerance toward the central nervous system during young adulthood
.
Proc Natl Acad Sci USA
.
2017
Oct
;
114
(
44
):
E9318
27
.
[PubMed]
0027-8424
67.
Aron-Wisnewsky
J
,
Doré
J
,
Clement
K
.
The importance of the gut microbiota after bariatric surgery
.
Nat Rev Gastroenterol Hepatol
.
2012
Oct
;
9
(
10
):
590
8
.
[PubMed]
1759-5045
68.
He
B
,
Hoang
TK
,
Tian
X
,
Taylor
CM
,
Blanchard
E
,
Luo
M
, et al
Lactobacillus reuteri Reduces the Severity of Experimental Autoimmune Encephalomyelitis in Mice by Modulating Gut Microbiota
.
Front Immunol
.
2019
Mar
;
10
:
385
.
[PubMed]
1664-3224
69.
Murphy
R
,
Tsai
P
,
Jüllig
M
,
Liu
A
,
Plank
L
,
Booth
M
.
Differential Changes in Gut Microbiota After Gastric Bypass and Sleeve Gastrectomy Bariatric Surgery Vary According to Diabetes Remission
.
Obes Surg
.
2017
Apr
;
27
(
4
):
917
25
.
[PubMed]
0960-8923
70.
Kellerer
T
,
Brandl
B
,
Büttner
J
,
Lagkouvardos
I
,
Hauner
H
,
Skurk
T
.
Impact of Laparoscopic Sleeve Gastrectomy on Gut Permeability in Morbidly Obese Subjects
.
Obes Surg
.
2019
Jul
;
29
(
7
):
2132
43
.
[PubMed]
0960-8923
71.
Brenton
JN
,
Banwell
B
,
Bergqvist
AG
,
Lehner-Gulotta
D
,
Gampper
L
,
Leytham
E
, et al
Pilot study of a ketogenic diet in relapsing-remitting MS
.
Neurol Neuroimmunol Neuroinflamm
.
2019
Apr
;
6
(
4
):
e565
.
[PubMed]
2332-7812
72.
Choi
IY
,
Piccio
L
,
Childress
P
,
Bollman
B
,
Ghosh
A
,
Brandhorst
S
, et al
A Diet Mimicking Fasting Promotes Regeneration and Reduces Autoimmunity and Multiple Sclerosis Symptoms
.
Cell Rep
.
2016
Jun
;
15
(
10
):
2136
46
.
[PubMed]
2639-1856
73.
Choi
IY
,
Lee
C
,
Longo
VD
.
Nutrition and fasting mimicking diets in the prevention and treatment of autoimmune diseases and immunosenescence
.
Mol Cell Endocrinol
.
2017
Nov
;
455
:
4
12
.
[PubMed]
0303-7207

Additional information

S.A. and R.M.-R. contributed equally as first authors.

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