Cytotherapy, 2014; 16: 402e405

Amyotrophic lateral sclerosis in pregnancy: clinical outcome duringthe post-partum period after stem cell transplantation into the frontalmotor cortex

HECTOR R. MARTÍNEZ1,2,3, SERGIO SALAZAR MARIONI3,C�ESAR E. ESCAMILLA OCAÑAS3, MARÍA TERESA GONZALEZ GARZA3 &JORGE E. MORENO-CUEVAS3

1Instituto de Neurología y Neurocirugía, Centro M�edico Zambrano Hellion, San Pedro, 2Servicio de Neurología,Hospital San Jose TEC de Monterrey, Monterrey, and 3Cellular Therapy Department, CITES Medical SchoolTecnológico de Monterrey, Monterrey, Mexico

AbstractBackground aims. Amyotrophic lateral sclerosis (ALS) is rare in pregnant patients. Stem cell therapy has been proposed as apotential therapeutic strategy for ALS. Methods. We describe a young woman with sporadic ALS that started during thesecond trimester of pregnancy with a rapid progression after delivery and severe motor impairment. Several drugs and stemcell injection by lumbar puncture were performed without changes before the patient was referred to our institution. Results.After bilateral autologous stem cell transplantation into the frontal motor cortices, we observed stabilization in ALS func-tional rating scale, significant delay of ALS progression and an extension in her life expectancy. Conclusions. Stem celltransplantation may alter the clinical course of ALS and improve quality of life in pre-menopausal women.

Key Words: ALS, pregnancy, stem-cell transplant

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal pro-gressive neurodegenerative disease. Its clinical featuresare attributable to the superimposition of motor defi-cits occurring in the upper motor neurons and lowermotor neurons. The onset of ALS is most frequentlyobserved in older adults 55e75 years old (1). Mani-festation of ALS is unusual in patients <40 years old;its manifestation in women of childbearing age is aninfrequent event (2).

Pregnancy often renders treatment complex.Several different therapeutic options have beenemployed, mainly pharmaceutical; however, stem celltherapy remains an unexplored method. We describea patient with ALS who experiencedmotor symptomsbeginning in the second trimester of pregnancy. Aftera normal delivery, this patient was treated with stemcell transplantation into the frontal motor cortices.

Case report

A 37-year-old primigravida presented with progres-sive upper left limb weakness that was first noticed at

Correspondence:Hector R. Martinez, MD, PhD, Batallon de San Patricio, No. 1E-mail: hector.ramon@itesm.mx

(Received 28 June 2013; accepted 1 November 2013)

ISSN 1465-3249 Copyright � 2014, International Society for Cellular Therapy. Phttp://dx.doi.org/10.1016/j.jcyt.2013.11.002

the ninth week of gestation and remained stableduring pregnancy. She denied any family history ofneuromuscular disorders. She was not taking anymedication and denied a recent history of toxinexposure. In March 2011, at 38 weeks’ gestation, shedelivered by cesarean section a healthy boy weighing3200 g; Apgar score was 10 at 1 min and 5 min. Thechild remains healthy and without complications atthe present time.

After delivery, clinical impairment progressed;the diagnosis of ALS was established according to ElEscorial clinical and neurophysiologic criteria (3).The patient developed cramps in the neck and upperextremities with increased weakness. Neurologicexamination revealed 3/5 and 4/5 weakness in theproximal and distal upper limbs, respectively, with asplit-hand syndrome; strength in the legs remainednormal. Cranial nerve examination was relevant forintermittent tongue fasciculations. Stretch reflexeswere normal. Bilateral Hoffmann, left Babinski andChaddock signs were detected. Sensory tests withpin, cold, vibration, and proprioception were alsonormal.

12 Colonia Residencial, San Agustin, San Pedro Garza Garcia, NL, Mexico.

ublished by Elsevier Inc. All rights reserved.

ALS in pregnancy: outcome after stem cell transplant 403

Over the following 2 months, the patient’s clinicalcondition deteriorated rapidly. Weakness increased1/5 and 3/5 in the left and right upper limbs, respec-tively, and 4/5 in the lower extremities. Tongue at-rophy, fasciculations and increase in salivationbecame evident; speech and deglutition were spared.She reported difficulties in walking, climbing stairs,and increasing clumsiness in the hands. In August2011, the patient underwent an autologous intra-thecal stem cell transplant at a different institution,without any changes in her progressive deteriorationrated by ALS Functional Rating Scale-revised(ALSFRS-r).

By December 2011, she had lost all motorfunction in the left upper limb, and bilateral armfasciculations were observed. Strength in the lowerextremities was 2/4. She had difficulty lifting herhead and torso in bed. Her respiratory function atrest remained normal. The institutional reviewboard of the Neurology and Neurosurgery Institute,Tecnológico de Monterrey, approved inclusion ofthe patient in the autologous stem cell transplantresearch protocol. After informed consent was ob-tained, she received a subcutaneous daily doseof 300 mg filgrastim (Neupogen; F. Hoffmann-LaRoche, Basel, Switzerland) for 3 days. The day afterthe final dose, peripheral blood mononuclear cellswere obtained by leukapheresis (Fenwal CS 3000Plus; Baxter International, Deerfield, IL, USA).The cell suspension was conjugated with anti-hu-man CD133þ superparamagnetic micro-beads, andlinked cells were isolated in a magnetic field over aMiniMACS separation column (Miltenyi Biotech,Bergisch Gladbach, Germany). The isolated CD133þ

stem cells (2.5 � 105) from peripheral blood weresuspended in 0.3 mL of the patient’s cerebrospinalfluid in sterile tubes (4,5).

Figure 1. T1-weighted magnetic resonance images in axial view obtainedfrontal motor stripes where stem cells were transplanted.

On June 12, 2012, bilateral stem cell trans-plantation was performed in the frontal motor cortexwith neuronavigation guidance (Vector Vision 2;BrainLab AG, Munich, Germany). The procedurewas performed under local anesthesia. No adverseevents were registered. Magnetic resonance imagingconfirmed the location of the transplant (Figure 1).During the following 6 months after transplantation,ALSFRS-r score remained stable with no decre-ments. At the end of January 2013, she suddenlypresented with respiratory arrest and a generalizedseizure, downgrading the ALFRS-r score to 9 points.Tracheostomy and gastrostomy were conducted.At 1 year after transplantation, she remains at homewith ventilatory support.

Discussion

ALS rarely occurs in pregnant women. There havebeen only 17 women with 18 pregnancies reported inthe English literature since 1956 (6e16), includingthe present patient. In this case, the patient firstexperienced symptoms during the second trimesterof pregnancy, and a definite diagnosis of ALS wasmade 2 months after delivery. Our patient’s courseresembled cases of rapid progression (13), withALSFRS-r scores decreasing 20 points over thecourse of 8 months after delivery, without anyresponse to pharmaceutical or inthrathecal stem cellapproaches.

Several treatments have been tested in pregnantpatients with ALS (2). So far, stem cell therapy hasnot been described in these patients. The inclusionof the patient in the present case in stem cell therapyprotocols was decided as a last resort. An inthra-thecal stem cell transplant was performed 5 monthsafter delivery; the patient showed no clinical

24 h after stem cell transplantation. Signal void is observed in the

Figure 2. ALSFRS-r scores during the follow-up period of a pregnant woman with ALS after stem cell transplantation into the frontal motorcortices compared with 10 control subjects with ALS treated with a pharmacologic approach.

404 H. R. Martínez et al.

improvement, and a sharp progression of the diseasewas observed. At 15 months after delivery, bilateralautologous stem cell transplantation into the frontalmotor cortex was performed under local anesthesiawith no adverse effects. During the next 6 months,the patient’s clinical condition stabilized, with nofluctuations in ALFRS-r scores since delivery. Afterstem cell transplantation into the upper motorcortices, the patient reported an increase in overallmuscle strength and feeling more invigorated.Objectively, stabilization of clinical function and aslight improvement in quality of life were notedcompared with a control group comprising 10 pa-tients with ALS who were treated pharmacologically(Figure 2) (5).

ALS is characterized by rapid clinical deteriora-tion; in our case presented here, stem cell trans-plantation resulted in a delay of progression andbetter quality of life compared with previous treat-ment approaches including pharmacologic treat-ment; however, a postoperative placebo effect cannotbe ruled out. Whether pregnancy influences thecourse of ALS remains speculative. No conclusivearguments have been made regarding this matter.Some reports have described pregnant patients withALS who had normal progression and deliveries(7e10); nevertheless, other studies suggested thatpregnancy exacerbates the deterioration and worsensthe prognosis of ALS.

In conclusion, although this report proposes thatstem cell transplantation into the frontal motorcortices may delay progression in post-partum pa-tients with ALS, further studies and trials are neces-sary to define the effectiveness of stem cell therapy.

Disclosure of interest: The authors have no com-mercial, proprietary or financial interest in theproducts or companies described in this article.

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