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Inflammatory demyelinating diseases of the central nervous system in Niger
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Brief Report
Inflammatory demyelinating diseases of the central nervous system in Niger H. Assadeck a,b,*, M. Toudou Daouda a,*, E´. Adehossi Omar a,b, Z. Mamadou a, F. Hassane Djibo a, D. Douma Maiga a,b a b
Service de me´decine interne et spe´cialite´s me´dicales, Hoˆpital National de Niamey, BP 238, Niamey, Niger Faculte´ des sciences de la sante´, Universite´ Abdou Moumouni de Niamey, Niamey, Niger
info article
abstract
Article history:
Background. – In sub-Saharan Africa (SSA), few studies have been reported on inflammatory
Received 25 March 2018
demyelinating diseases of the central nervous system (CNS). Neuromyelitis optica spectrum
Received in revised form
disorders (NMOSD) seems to be the most frequent inflammatory demyelinating disease of
13 May 2018
CNS in sub-Saharan Africans or people of sub-Saharan African descent.
Accepted 24 May 2018
Methods. – We report the observations of seven patients from Niger diagnosed with inflam-
Available online xxx
matory demyelinating diseases of CNS over a period of 21 years (1996–2017). Results. – They were four women and three men aged 19 to 66 years (mean age: 37 years),
Keywords:
with no known past medical history. Four patients were diagnosed with NMOSD (2 men and
Neuromyelitis optica spectrum
2 women) and the three other patients with multiple sclerosis (MS, 2 women and 1 man). The
disorders
three patients diagnosed with MS had the relapsing-remitting form. The cerebrospinal fluid
Multiple sclerosis
study revealed the presence of oligoclonal bands in the three patients. Of the patients
Magnetic resonance imaging
diagnosed with NMOSD, two patients negative anti-aquaporin 4 antibodies (anti-MOG
Epidemiology
antibodies not done), one of whom had bilateral optic neuritis (ON) with longitudinally
Hospital
extensive transverse myelitis (LETM) and the other unilateral ON with LETM. Two patients
Niamey
with MS were treated with interferon beta-1a and the third patient with azathioprine. The
Niger
Expanded Disability Status Scale ranged from 1 to 2 in these three patients at the time of
Sub-Saharan Africa
initiation of background treatment. Azathioprine was the treatment prescribed in the four patients with NMOSD. We did not find any case of acute disseminated encephalomyelitis. Conclusion. – Our case series suggests the rarity of inflammatory demyelinating diseases of CNS in Niger, and NMOSD seems to be more frequent than MS. # 2018 Elsevier Masson SAS. All rights reserved.
1.
Introduction
Inflammatory demyelinating diseases of the central nervous system (CNS) are relatively common in sub-Saharan Africa
(SSA), but their prevalence remains unknown. Few studies have been reported on inflammatory demyelinating diseases of CNS in SSA, and these studies are essentially case series [1– 7]. Neuromyelitis optica spectrum disorders (NMOSD) seem to be more frequent than multiple sclerosis (MS) in sub-Saharan
* Corresponding authors: Service de me´decine interne et spe´cialite´s me´dicales, Hoˆpital National de Niamey, BP 238, Niamey, Niger. E-mail addresses: [email protected] (H. Assadeck), [email protected] (M. Toudou Daouda). https://doi.org/10.1016/j.neurol.2018.05.003 0035-3787/# 2018 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Assadeck H, et al. Inflammatory demyelinating diseases of the central nervous system in Niger. Revue neurologique (2018), https://doi.org/10.1016/j.neurol.2018.05.003
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Africans [1,8–10]. Acute disseminated encephalomyelitis (ADEM) is the least described inflammatory demyelinating disease in SSA [11]. We report the demographic, clinical, paraclinical and therapeutic features of seven cases of inflammatory demyelinating diseases of CNS observed in Niger.
2.
Methods
We collected retrospectively the observations of seven patients from Niger diagnosed with inflammatory demyelinating diseases of CNS over a period of 21 years (1996–2017). Three observations had been previously published [7,12]. Each patient had benefited from cerebrospinal magnetic resonance imaging (MRI) and exhaustive explorations, including, according to the case, systemic immunological tests, dosage of angiotensin-converting enzyme (ACE) and vitamin B12, serological tests for syphilis, Lyme disease, human immunodeficiency virus (HIV), hepatitis C and hepatitis B, search for tuberculosis infection, thyroid function tests and determination of anti-aquaporin 4 antibodies.
3.
Results
They were four women and three men aged 19 to 66 years (mean age: 37 years), with no known past medical history. Four patients were diagnosed with NMOSD (2 men and 2 women) and the three other patients with MS (2 women and 1 man). Table 1 summarizes the demographic, clinical, radiological and therapeutic features of the seven patients.
3.1.
Multiple sclerosis
3.1.1.
Case no81 (Assadeck et al., 2018 [7])
A 19-year-old woman, of Hausa origin, with no known past medical history, presented in May 2014 with paresthesia and rapid onset weakness of the left hemi-body that began five days before consultation. The detailed interrogation of the patient found six months earlier, in December 2013, a notion of urinary leakage and weakness of the lower right limb which had regressed spontaneously in 14 days. On admission, the physical examination revealed left hemiparesis, left facial paralysis, left hemihypoesthesia, and exaggerated tendon reflexes to all four limbs. The brain CT-scan revealed no particular abnormality. The cerebral magnetic resonance imaging (MRI) showed periventricular and juxtacortical rounded lesions with clear limits in hypersignal on Fluid Attenuated Inversion Recovery (FLAIR) images and another lesion in the right cerebral peduncle. There was no gadolinium enhancement for all lesions. Spinal cord MRI did not find any signal abnormalities. The MRI abnormalities and the clinical history of our patient, made us to discuss the diagnosis of an inflammatory demyelinating disease of the CNS, especially MS. The cerebrospinal fluid (CSF) study revealed the presence of oligoclonal bands, without meningitis or hyperproteinorachia. Evoked visual potentials were normal. Antinuclear antibodies, antidouble-stranded DNA (anti-dsDNA), anti-Sjo¨gren’s syndrome
types A and B (anti-SSA and anti-SSB) and antiphospholipid antibodies, as well as the dosage of vitamin B12 and angiotensinconverting enzyme (ACE), were all normal. Serological tests for syphilis, Lyme disease, human immunodeficiency virus (HIV), hepatitis C and hepatitis B were also negative. At the end of these analyzes, the diagnosis of relapsing-remitting MS was retained according to the McDonald’s revised criteria for diagnosis of MS [13]. The patient was treated with pulse intravenous methylprednisolone (1 g/day for 3 days) with improvement of symptoms with an Expanded Disability Status Scale (EDSS) scored 2 at three months. Interferon beta-1a has been initiated as long-term treatment.
3.1.2.
Case no82 (Assadeck et al., 2018 [7])
A 46-year-old man, of Zarma origin, with no known past medical history, presented in 1990, at the age of 19 years, with sudden onset left blindness that had regressed partially after a few days without any treatment. In 2000 (10 years later), the patient presented paresthesia and rapidly progressive weakness of the right hemi-body over three days, with spontaneous complete recovery in three weeks. In April 2016, the patient presented again with sudden onset weakness of the right hemi-body that had started seven days before admission. The neurological examination found right hemiparesis, right hemihypoesthesia, and exaggerated tendon reflexes to all four limbs. The ophthalmologic examination found a visual acuity of 5/10 on the left eye and 10/10 on the right eye with normal fundus examination. The brain MRI showed periventricular and juxtacortical lesions in hypersignal on T2weighted images and FLAIR images. There was no gadolinium enhancement for all lesions. Spinal cord MRI did not find any signal abnormalities. The CSF study revealed the presence of oligoclonal bands, without meningitis or hyperproteinorachia. Antinuclear antibodies, anti-dsDNA, anti-SSA, anti-SSB, and antiphospholipid antibodies were normal. Serological tests for syphilis, HIV, hepatitis C and hepatitis B were negative. Vitamin B12 and ACE levels were normal. The diagnosis of relapsing-remitting MS was retained. The patient was treated with pulse intravenous methylprednisolone (1 g/day for 5 days) with improvement of symptoms. Interferon beta-1a has been initiated as long-term treatment with an initial EDSS at 2.
3.1.3.
Case no83
A 24-year-old woman, of Hausa origin, with no known past medical history, presented in January 2013, at the age of 22 years, with progressive onset weakness of the lower right limb over three days with spontaneous regression over one month. In June 2015 (2 years later), the patient presented paresthesia and progressive onset weakness of the left leg that had started six weeks before admission. The neurologic examination revealed left crural monoparesis, left crural hypopallesthesia, left hemi-ataxia, and exaggerated tendon reflexes in all four limbs with bilateral Babinski sign. The brain MRI showed rounded periventricular and juxtacortical lesions with clear limits in hypersignal on FLAIR images, without gadolinium enhancement for all lesions (Fig. 1). Spinal cord MRI did not find any signal abnormalities. The CSF study revealed the presence of oligoclonal bands, without pleiocytosis or hyperproteinorachia. Serological tests for syphilis,
Please cite this article in press as: Assadeck H, et al. Inflammatory demyelinating diseases of the central nervous system in Niger. Revue neurologique (2018), https://doi.org/10.1016/j.neurol.2018.05.003
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Table 1 – Demographic, clinical and radiological features of the 7 patients. Patients
Sex/Age (years)
Origin
Clinical signs
1
F/19
Hausa
Left hemiparesis, left facial paralysis, left hemihypoesthesia
2
M/46
Zarma
Right hemiparesis, right hemihypoesthesia, left optic neuritis
3
F/24
Hausa
4
M/66
Hausa
Left crural monoparesis, left crural hypopallesthesia, left hemi-ataxia Quadriplegia predominant in the lower limbs with sensory level D3
5
F/41
Zarma
Tetraparesis, errors in the sense of position of the big toes, left optic neuritis
No
6
F/37
Touareg
No
7
M/26
Zarma
tetraparesis predominant in the lower limbs, errors in the sense of position of the big toes, bilateral optic neuritis Flaccid quadriplegia with cervical sensory level
MRI
Diagnosis
Treatment
Cerebral lesions
Medullary lesions
Periventricular and juxtacortical rounded lesions with clear limits in hypersignal on FLAIR images, and in the right cerebral peduncle, without gadolinium enhancement for all these lesions Periventricular and juxtacortical lesions in hypersignal on FLAIR images, without gadolinium enhancement Periventricular and juxtacortical lesions in hypersignal on FLAIR images, without gadolinium enhancement Non-specific left parietal cortical lesion
No
MS
Interferon beta-1a
No
MS
Interferon beta-1a
No
MS
Azathioprine
Transverse cervical myelitis, extending from C6 to D3, with gadolinium enhancement Transverse cervical myelitis, hyperintense on T2weighted images and extending from bulbo-spinal junction to C7 Extensive medullary lesion in hypersignal T2 affecting the area postrema
NMOSD with AQP4-IgG
Azathioprine
NMOSD without AQP4-IgG
Azathioprine
NMOSD without AQP4-IgG
Azathioprine
NMOSD with AQP4-IgG
Azathioprine
Transverse cervical myelitis, hyperintense on T2weighted images and extending from C2 to C5, with gadolinium enhancement
No
F: female; M: male; MRI: magnetic resonance imaging; MS: multiple sclerosis; NMOSD: neuromyelitis optica spectrum disorders; AQP4: aquaporin 4; IgG: immunoglobulin G; FLAIR: Fluid Attenuated Inversion Recovery.
HIV, hepatitis C and hepatitis B were negative. Vitamin B12 and ACE levels were normal. Soluble anti-nuclear antigen antibodies, anti-dsDNA, anti-Smith (anti-Sm), anti-SSA, antiSSB, and antineutrophil cytoplasmic antibodies (ANCA) were negative, except antinuclear antibodies that were weakly positive. The thyroid function tests including antithyroglobulin (anti-TG) antibodies, antithyroperoxidase (anti-TPO), antiTSH receptor antibodies, TSH, T3 and T4 were normal. The diagnosis of relapsing-remitting MS was retained. The patient was treated with pulse intravenous methylprednisolone (1 g/day for 3 days), and then azathiorprine was initiated as long-term treatment with an initial EDSS at 1.
4.
Neuromyelitis optica spectrum disorders
4.1.
Case no84 (Assadeck et al., 2017 [12])
A 66-year-old man, of Hausa origin, with no known past medical history, consulted in May 2017 for rapidly progressive limb weakness associated with vesico-sphincteral disorders with urinary incontinence. He reported no history of trauma of the spine, or fever or exposure to chemical or toxic products. On admission, neurological examination found an areflexic quadriplegia predominant in the lower limbs, associated with sensory level D3. He did not report visual disturbances since
Please cite this article in press as: Assadeck H, et al. Inflammatory demyelinating diseases of the central nervous system in Niger. Revue neurologique (2018), https://doi.org/10.1016/j.neurol.2018.05.003
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Fig. 1 – Brain magnetic resonance imaging (MRI), Fluid Attenuated Inversion Recovery (FLAIR) images (A, B): patient 3. Periventricular and juxtacortical rounded lesions with clear limits in hypersignal.
the onset of symptoms. He did not report recent or previous visual disturbances as well as sensory and motor disorders. Spinal cord MRI showed transverse cervical myelitis, hyperintense on T2-weighted images and extending from C6 to D3, and isointense on T1-weighted images, with enhancement on gadolinium administration. The brain MRI showed a nonspecific left parietal cortical lesion. The CSF study was normal. Immunological tests revealed positive anti-AQP4 antibodies by using indirect immunofluorescence of transfected cells, with positive antinuclear antibodies. Anti-dsDNA antibodies, anti-Sm, anti-SSA, anti-SSB, and antiphospholipid antibodies, as well as the dosage of ACE, were all normal. Serological tests for syphilis, HIV, hepatitis C and hepatitis B were also negative. The thyroid function tests including anti-TG antibodies, antiTPO, anti-TSH receptor antibodies, TSH, T3 and T4 were normal. Evoked visual potentials were normal. The search for pulmonary and extrapulmonary tuberculosis (Chest X-ray, mycobacterium tuberculosis) was negative. At the end of these analyses, a diagnosis of NMOSD with AQP4-IgG was retained according to the international consensus diagnostic criteria for NMOSD [14]. The patient was treated with pulse intravenous methylprednisolone (1 g/day for 10 days), with no clinical improvement. Azathiorprine has been initiated as long-term treatment.
4.2.
Case no85
A 41-year-old woman, of Zarma origin, with no known past medical history, presented in April 2012 with progressive onset diminution of vision of the left eye associated with retroorbital pain during eye movements. Ophthalmologic examination revealed left visual acuity at 2/10 with a normal fundus examination. The patient was treated with oral corticosteroid therapy (1 mg/kg/day for 2 weeks) for left retrobulbar optic neuritis with partial improvement. In July 2016, the patient presented paresthesia and muscle weakness of all four limbs. On admission, the neurological examination revealed tetra-
pararesis associated with errors in the sense of position of the big toes, exaggerated tendon reflexes to all four limbs with bilateral Babinski sign, and visual acuity of the left eye at 4/10. Spinal cord MRI showed a transverse cervical myelitis, hyperintense on T2-weighted images and extending from bulbo-spinal junction to C7, without gadolinium enhancement (Fig. 2). The brain MRI did not find any signal abnormalities. The CSF study was normal. Serological tests for syphilis, HIV, hepatitis C and hepatitis B were negative. Soluble anti-nuclear antigen antibodies, antinuclear antibodies, anti-dsDNA, anti-SSA, anti-SSB and anti-AQP4 were normal. Detection of anti-myelin oligodendrocyte glycoprotein (anti-MOG) antibodies was not done. The search for pulmonary and extrapulmonary tuberculosis was negative. The diagnosis of NMOSD without AQP4-IgG was retained, and the patient was treated with pulse intravenous methylprednisolone (1 g/day for 3 days). Azathiorprine has been initiated as long-term treatment.
4.3.
Case no86
A 37-year-old woman, of Touareg origin, with no known past medical history, presented in July 2015 with rapidly progressive bilateral blindness over two days, not improved by the oral corticosteroid therapy (1 mg/kg/day for 2 weeks). In September 2017, the patient presented weakness of all four limbs associated with a hiccup, five weeks before admission. The neurological examination found tetraparesis predominant in the lower limbs, errors in the sense of position of the big toes, and bilateral blindness with abolition of the photomotor reflex. Spinal cord MRI showed an extensive medullary lesion in hypersignal T2 affecting the area postrema, without gadolinium enhancement (Fig. 3). The brain MRI did not find any signal abnormalities. The CSF study revealed a white blood cell count at 11/m3, with glucose at 0.67 g/L and protein at 0.42 g/L, without presence of oligoclonal bands. Serological tests for syphilis, HIV, hepatitis C and hepatitis B were
Please cite this article in press as: Assadeck H, et al. Inflammatory demyelinating diseases of the central nervous system in Niger. Revue neurologique (2018), https://doi.org/10.1016/j.neurol.2018.05.003
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Fig. 2 – Spinal-cord MRI, T2-weighted images (A, B): patient 5. Hyperintense lesion of the cervical spinal cord extending from bulbo-spinal junction to C7.
Fig. 3 – Spinal-cord MRI, T2-weighted images (A, B): patient 6. Hyperintense lesions of the cervical spinal and area postrema.
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negative. The dosage of vitamin B12 and ACE was normal. Antinuclear antibodies, anti-dsDNA, anti-SSA, anti-SSB and anti-AQP4 were normal as well as the search for tuberculosis infection. The diagnosis of NMOSD without AQP4-IgG was retained. The patient was treated with pulse intravenous methylprednisolone (1 g/day for 5 days), with partial clinical improvement, and then azathiorprine was started as long-term treatment.
4.4.
Case no87
A 26-year-old man, of Zarma origin, with no known past medical history, consulted for weakness of all four limbs with urinary incontinence that had started 10 days before admission. The neurological examination found a flaccid quadriplegia associated with a cervical sensory level. Spinal cord MRI showed transverse cervical myelitis, hyperintense on T2weighted images and extending from C2 to C5, without gadolinium enhancement (Fig. 4). The brain MRI did not find any signal abnormalities. The CSF study was normal. AntiAQP4 antibodies were positive. Antinuclear antibodies, antidsDNA, anti-SSA, and anti-SSB were normal as well as the search for tuberculosis infection. The thyroid function tests including anti-TG antibodies, anti-TPO, anti-TSH receptor antibodies, TSH, T3 and T4 were normal. Serological tests for syphilis, HIV, hepatitis C and hepatitis B were negative. The dosage of vitamin B12 and ACE was normal. The diagnosis of NMOSD with AQP4-IgG was retained. The patient was treated with pulse intravenous methylpredniso-
lone (1 g/day for 10 days), without any clinical improvement. Azathiorprine was started as long-term treatment.
5.
Discussion
We report a case series of patients from Niger who had never left the country before, diagnosed with inflammatory demyelinating diseases of CNS over a period of 21 years (1996–2017). Three patients were diagnosed with MS and the four others with NMOSD. After ruling out other etiologies with similar clinical pictures, the diagnosis of MS had been considered in our three patients according to the revised criteria of McDonald 2010 [13]. With respect to the NMOSD, the diagnosis was considered according to the international consensus diagnostic criteria for NMOSD [14]. We did not find any case of ADEM in this study. Our case series suggests the rarity of inflammatory demyelinating diseases of CNS in Niger, and NMOSD seems to be more frequent than MS. This higher susceptibility to NMOSD than to MS among sub-Saharan Africans has been reported previously by several authors [1,8–10]. In 2009, a Cuban study showed that the prevalence of NMOSD is higher among Afro-Cubans (0.69/100,000 inhabitants) than among Hispano-Cubans (0.42/100,000 inhabitants) [15]. In the French West Indies, populations mainly consituted by people of subSaharan African descent, a high prevalence of NMOSD (10/ 100,000 inhabitants) has been reported, suggesting a high susceptibility of people of sub-Saharan African descent to the NMOSD [16]. However, in 2012, an American multicenter study
Fig. 4 – Spinal-cord MRI, T2-weighted images (A, B): patient 7. Hyperintense lesion of the cervical spinal cord extending from C2 to C5.
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did not show this predominance of NMOSD among Americans of sub-Saharan African descent compared to white Americans [17]. The susceptibility of sub-Saharan Africans to the NMOSD could be due to the existence of environmental factors predisposing to NMOSD in SSA. Several microorganisms, which are common in SSA, have been reported in patients with NMOSD, among which the most frequently reported were mycobacterium tuberculosis, HIV, HTLV1, HHV, VZV, EBV, CMV [18]. Exposure to these microorganisms activates T and B cells. Activation of B cells produces antibodies directed against microorganisms, which interact by cross reaction with AQP4 causing injuries of tissues with high expression in AQP4 [19]. Genetic factors predisposing to NMOSD have also been reported. The genetic factor most extensively studied is the HLA. Blanco et al. [20] demonstrated that the frequency of HLA-DRB1*03 allele is significantly higher in patients with NMOSD than in healthy controls. Thus, studies had shown a high frequency of HLA-DRB1*03 allele in French Afro-Caribbean and Afro-Brazilian patients with NMOSD [21,22]. This genetic factor could also explain the susceptibility of subSaharan Africans to NMOSD. The low prevalence of MS among sub-Saharan Africans links to the existence of protective environmental factors against the risk of MS in tropical regions. The high levels of exposure to ultraviolet radiations in the tropical regions represent the most important protective environmental factor [23–25]. Ultraviolet radiations reduce the risk of MS by inducing the production of vitamin D3 in the cutaneous cells. Vitamin D3 induces a decrease of Th1 lymphocytes response, thus suppressing the increased production of interferon g, IL2 and TNFa which have a pro-inflammatory activity, and favors the Th2 lymphocytes response that produce IL4, IL5, IL6, IL10 and IL13 which have an anti-inflammatory activity and therefore a reduction of the risk of MS [26,27]. Intestinal parasitosis (helminthiasis, schistosomiasis, ascariasis, etc.) and some bacteria (Prevotella, Ruminococcus, Helicobacter pylori, some mycobacteria, etc.) represent the second protective environmental factor against MS [28–30]. Exposure to these microorganisms induces decreased activity of the immune system by activation of Th2 lymphocyte response [29,30]. In addition, helminth infection activates CD4CD25(+) FOXP3(+) T cells that induce Th2 lymphocytes response by suppressing Th1 lymphocyte response [31]. The unequal distribution of the prevalence of MS between different social groups in the same population, exposed to the same environmental factors suggests the implication of genetic factors in the pathogenesis of MS [7]. Thus, studies have shown that the prevalence of MS is lower among AfricoAmericans compared to white Americans [32,33]. In addition, Bhigjee et al. [34] showed in 2007 in South Africa a higher prevalence of MS among white South Africans compared to blacks. These data suggest the low risk of MS in black people.
6.
Conclusion
Our case series shows that inflammatory demyelinating diseases of CNS are rare in Niger, and NMOSD seems to be more frequent than MS. The prevalence and incidence of these diseases were unknown in Niger. A prospective epidemiological study in the
7
general population is needed to clarify the prevalence and incidence of MS and NMOSD in Nigerien populations.
Funding This study did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Disclosure of interest The authors declare that they have no competing interest.
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Brief Report
Inflammatory demyelinating diseases of the central nervous system in Niger H. Assadeck a,b,*, M. Toudou Daouda a,*, E´. Adehossi Omar a,b, Z. Mamadou a, F. Hassane Djibo a, D. Douma Maiga a,b a b
Service de me´decine interne et spe´cialite´s me´dicales, Hoˆpital National de Niamey, BP 238, Niamey, Niger Faculte´ des sciences de la sante´, Universite´ Abdou Moumouni de Niamey, Niamey, Niger
info article
abstract
Article history:
Background. – In sub-Saharan Africa (SSA), few studies have been reported on inflammatory
Received 25 March 2018
demyelinating diseases of the central nervous system (CNS). Neuromyelitis optica spectrum
Received in revised form
disorders (NMOSD) seems to be the most frequent inflammatory demyelinating disease of
13 May 2018
CNS in sub-Saharan Africans or people of sub-Saharan African descent.
Accepted 24 May 2018
Methods. – We report the observations of seven patients from Niger diagnosed with inflam-
Available online xxx
matory demyelinating diseases of CNS over a period of 21 years (1996–2017). Results. – They were four women and three men aged 19 to 66 years (mean age: 37 years),
Keywords:
with no known past medical history. Four patients were diagnosed with NMOSD (2 men and
Neuromyelitis optica spectrum
2 women) and the three other patients with multiple sclerosis (MS, 2 women and 1 man). The
disorders
three patients diagnosed with MS had the relapsing-remitting form. The cerebrospinal fluid
Multiple sclerosis
study revealed the presence of oligoclonal bands in the three patients. Of the patients
Magnetic resonance imaging
diagnosed with NMOSD, two patients negative anti-aquaporin 4 antibodies (anti-MOG
Epidemiology
antibodies not done), one of whom had bilateral optic neuritis (ON) with longitudinally
Hospital
extensive transverse myelitis (LETM) and the other unilateral ON with LETM. Two patients
Niamey
with MS were treated with interferon beta-1a and the third patient with azathioprine. The
Niger
Expanded Disability Status Scale ranged from 1 to 2 in these three patients at the time of
Sub-Saharan Africa
initiation of background treatment. Azathioprine was the treatment prescribed in the four patients with NMOSD. We did not find any case of acute disseminated encephalomyelitis. Conclusion. – Our case series suggests the rarity of inflammatory demyelinating diseases of CNS in Niger, and NMOSD seems to be more frequent than MS. # 2018 Elsevier Masson SAS. All rights reserved.
1.
Introduction
Inflammatory demyelinating diseases of the central nervous system (CNS) are relatively common in sub-Saharan Africa
(SSA), but their prevalence remains unknown. Few studies have been reported on inflammatory demyelinating diseases of CNS in SSA, and these studies are essentially case series [1– 7]. Neuromyelitis optica spectrum disorders (NMOSD) seem to be more frequent than multiple sclerosis (MS) in sub-Saharan
* Corresponding authors: Service de me´decine interne et spe´cialite´s me´dicales, Hoˆpital National de Niamey, BP 238, Niamey, Niger. E-mail addresses: [email protected] (H. Assadeck), [email protected] (M. Toudou Daouda). https://doi.org/10.1016/j.neurol.2018.05.003 0035-3787/# 2018 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Assadeck H, et al. Inflammatory demyelinating diseases of the central nervous system in Niger. Revue neurologique (2018), https://doi.org/10.1016/j.neurol.2018.05.003
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Africans [1,8–10]. Acute disseminated encephalomyelitis (ADEM) is the least described inflammatory demyelinating disease in SSA [11]. We report the demographic, clinical, paraclinical and therapeutic features of seven cases of inflammatory demyelinating diseases of CNS observed in Niger.
2.
Methods
We collected retrospectively the observations of seven patients from Niger diagnosed with inflammatory demyelinating diseases of CNS over a period of 21 years (1996–2017). Three observations had been previously published [7,12]. Each patient had benefited from cerebrospinal magnetic resonance imaging (MRI) and exhaustive explorations, including, according to the case, systemic immunological tests, dosage of angiotensin-converting enzyme (ACE) and vitamin B12, serological tests for syphilis, Lyme disease, human immunodeficiency virus (HIV), hepatitis C and hepatitis B, search for tuberculosis infection, thyroid function tests and determination of anti-aquaporin 4 antibodies.
3.
Results
They were four women and three men aged 19 to 66 years (mean age: 37 years), with no known past medical history. Four patients were diagnosed with NMOSD (2 men and 2 women) and the three other patients with MS (2 women and 1 man). Table 1 summarizes the demographic, clinical, radiological and therapeutic features of the seven patients.
3.1.
Multiple sclerosis
3.1.1.
Case no81 (Assadeck et al., 2018 [7])
A 19-year-old woman, of Hausa origin, with no known past medical history, presented in May 2014 with paresthesia and rapid onset weakness of the left hemi-body that began five days before consultation. The detailed interrogation of the patient found six months earlier, in December 2013, a notion of urinary leakage and weakness of the lower right limb which had regressed spontaneously in 14 days. On admission, the physical examination revealed left hemiparesis, left facial paralysis, left hemihypoesthesia, and exaggerated tendon reflexes to all four limbs. The brain CT-scan revealed no particular abnormality. The cerebral magnetic resonance imaging (MRI) showed periventricular and juxtacortical rounded lesions with clear limits in hypersignal on Fluid Attenuated Inversion Recovery (FLAIR) images and another lesion in the right cerebral peduncle. There was no gadolinium enhancement for all lesions. Spinal cord MRI did not find any signal abnormalities. The MRI abnormalities and the clinical history of our patient, made us to discuss the diagnosis of an inflammatory demyelinating disease of the CNS, especially MS. The cerebrospinal fluid (CSF) study revealed the presence of oligoclonal bands, without meningitis or hyperproteinorachia. Evoked visual potentials were normal. Antinuclear antibodies, antidouble-stranded DNA (anti-dsDNA), anti-Sjo¨gren’s syndrome
types A and B (anti-SSA and anti-SSB) and antiphospholipid antibodies, as well as the dosage of vitamin B12 and angiotensinconverting enzyme (ACE), were all normal. Serological tests for syphilis, Lyme disease, human immunodeficiency virus (HIV), hepatitis C and hepatitis B were also negative. At the end of these analyzes, the diagnosis of relapsing-remitting MS was retained according to the McDonald’s revised criteria for diagnosis of MS [13]. The patient was treated with pulse intravenous methylprednisolone (1 g/day for 3 days) with improvement of symptoms with an Expanded Disability Status Scale (EDSS) scored 2 at three months. Interferon beta-1a has been initiated as long-term treatment.
3.1.2.
Case no82 (Assadeck et al., 2018 [7])
A 46-year-old man, of Zarma origin, with no known past medical history, presented in 1990, at the age of 19 years, with sudden onset left blindness that had regressed partially after a few days without any treatment. In 2000 (10 years later), the patient presented paresthesia and rapidly progressive weakness of the right hemi-body over three days, with spontaneous complete recovery in three weeks. In April 2016, the patient presented again with sudden onset weakness of the right hemi-body that had started seven days before admission. The neurological examination found right hemiparesis, right hemihypoesthesia, and exaggerated tendon reflexes to all four limbs. The ophthalmologic examination found a visual acuity of 5/10 on the left eye and 10/10 on the right eye with normal fundus examination. The brain MRI showed periventricular and juxtacortical lesions in hypersignal on T2weighted images and FLAIR images. There was no gadolinium enhancement for all lesions. Spinal cord MRI did not find any signal abnormalities. The CSF study revealed the presence of oligoclonal bands, without meningitis or hyperproteinorachia. Antinuclear antibodies, anti-dsDNA, anti-SSA, anti-SSB, and antiphospholipid antibodies were normal. Serological tests for syphilis, HIV, hepatitis C and hepatitis B were negative. Vitamin B12 and ACE levels were normal. The diagnosis of relapsing-remitting MS was retained. The patient was treated with pulse intravenous methylprednisolone (1 g/day for 5 days) with improvement of symptoms. Interferon beta-1a has been initiated as long-term treatment with an initial EDSS at 2.
3.1.3.
Case no83
A 24-year-old woman, of Hausa origin, with no known past medical history, presented in January 2013, at the age of 22 years, with progressive onset weakness of the lower right limb over three days with spontaneous regression over one month. In June 2015 (2 years later), the patient presented paresthesia and progressive onset weakness of the left leg that had started six weeks before admission. The neurologic examination revealed left crural monoparesis, left crural hypopallesthesia, left hemi-ataxia, and exaggerated tendon reflexes in all four limbs with bilateral Babinski sign. The brain MRI showed rounded periventricular and juxtacortical lesions with clear limits in hypersignal on FLAIR images, without gadolinium enhancement for all lesions (Fig. 1). Spinal cord MRI did not find any signal abnormalities. The CSF study revealed the presence of oligoclonal bands, without pleiocytosis or hyperproteinorachia. Serological tests for syphilis,
Please cite this article in press as: Assadeck H, et al. Inflammatory demyelinating diseases of the central nervous system in Niger. Revue neurologique (2018), https://doi.org/10.1016/j.neurol.2018.05.003
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Table 1 – Demographic, clinical and radiological features of the 7 patients. Patients
Sex/Age (years)
Origin
Clinical signs
1
F/19
Hausa
Left hemiparesis, left facial paralysis, left hemihypoesthesia
2
M/46
Zarma
Right hemiparesis, right hemihypoesthesia, left optic neuritis
3
F/24
Hausa
4
M/66
Hausa
Left crural monoparesis, left crural hypopallesthesia, left hemi-ataxia Quadriplegia predominant in the lower limbs with sensory level D3
5
F/41
Zarma
Tetraparesis, errors in the sense of position of the big toes, left optic neuritis
No
6
F/37
Touareg
No
7
M/26
Zarma
tetraparesis predominant in the lower limbs, errors in the sense of position of the big toes, bilateral optic neuritis Flaccid quadriplegia with cervical sensory level
MRI
Diagnosis
Treatment
Cerebral lesions
Medullary lesions
Periventricular and juxtacortical rounded lesions with clear limits in hypersignal on FLAIR images, and in the right cerebral peduncle, without gadolinium enhancement for all these lesions Periventricular and juxtacortical lesions in hypersignal on FLAIR images, without gadolinium enhancement Periventricular and juxtacortical lesions in hypersignal on FLAIR images, without gadolinium enhancement Non-specific left parietal cortical lesion
No
MS
Interferon beta-1a
No
MS
Interferon beta-1a
No
MS
Azathioprine
Transverse cervical myelitis, extending from C6 to D3, with gadolinium enhancement Transverse cervical myelitis, hyperintense on T2weighted images and extending from bulbo-spinal junction to C7 Extensive medullary lesion in hypersignal T2 affecting the area postrema
NMOSD with AQP4-IgG
Azathioprine
NMOSD without AQP4-IgG
Azathioprine
NMOSD without AQP4-IgG
Azathioprine
NMOSD with AQP4-IgG
Azathioprine
Transverse cervical myelitis, hyperintense on T2weighted images and extending from C2 to C5, with gadolinium enhancement
No
F: female; M: male; MRI: magnetic resonance imaging; MS: multiple sclerosis; NMOSD: neuromyelitis optica spectrum disorders; AQP4: aquaporin 4; IgG: immunoglobulin G; FLAIR: Fluid Attenuated Inversion Recovery.
HIV, hepatitis C and hepatitis B were negative. Vitamin B12 and ACE levels were normal. Soluble anti-nuclear antigen antibodies, anti-dsDNA, anti-Smith (anti-Sm), anti-SSA, antiSSB, and antineutrophil cytoplasmic antibodies (ANCA) were negative, except antinuclear antibodies that were weakly positive. The thyroid function tests including antithyroglobulin (anti-TG) antibodies, antithyroperoxidase (anti-TPO), antiTSH receptor antibodies, TSH, T3 and T4 were normal. The diagnosis of relapsing-remitting MS was retained. The patient was treated with pulse intravenous methylprednisolone (1 g/day for 3 days), and then azathiorprine was initiated as long-term treatment with an initial EDSS at 1.
4.
Neuromyelitis optica spectrum disorders
4.1.
Case no84 (Assadeck et al., 2017 [12])
A 66-year-old man, of Hausa origin, with no known past medical history, consulted in May 2017 for rapidly progressive limb weakness associated with vesico-sphincteral disorders with urinary incontinence. He reported no history of trauma of the spine, or fever or exposure to chemical or toxic products. On admission, neurological examination found an areflexic quadriplegia predominant in the lower limbs, associated with sensory level D3. He did not report visual disturbances since
Please cite this article in press as: Assadeck H, et al. Inflammatory demyelinating diseases of the central nervous system in Niger. Revue neurologique (2018), https://doi.org/10.1016/j.neurol.2018.05.003
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Fig. 1 – Brain magnetic resonance imaging (MRI), Fluid Attenuated Inversion Recovery (FLAIR) images (A, B): patient 3. Periventricular and juxtacortical rounded lesions with clear limits in hypersignal.
the onset of symptoms. He did not report recent or previous visual disturbances as well as sensory and motor disorders. Spinal cord MRI showed transverse cervical myelitis, hyperintense on T2-weighted images and extending from C6 to D3, and isointense on T1-weighted images, with enhancement on gadolinium administration. The brain MRI showed a nonspecific left parietal cortical lesion. The CSF study was normal. Immunological tests revealed positive anti-AQP4 antibodies by using indirect immunofluorescence of transfected cells, with positive antinuclear antibodies. Anti-dsDNA antibodies, anti-Sm, anti-SSA, anti-SSB, and antiphospholipid antibodies, as well as the dosage of ACE, were all normal. Serological tests for syphilis, HIV, hepatitis C and hepatitis B were also negative. The thyroid function tests including anti-TG antibodies, antiTPO, anti-TSH receptor antibodies, TSH, T3 and T4 were normal. Evoked visual potentials were normal. The search for pulmonary and extrapulmonary tuberculosis (Chest X-ray, mycobacterium tuberculosis) was negative. At the end of these analyses, a diagnosis of NMOSD with AQP4-IgG was retained according to the international consensus diagnostic criteria for NMOSD [14]. The patient was treated with pulse intravenous methylprednisolone (1 g/day for 10 days), with no clinical improvement. Azathiorprine has been initiated as long-term treatment.
4.2.
Case no85
A 41-year-old woman, of Zarma origin, with no known past medical history, presented in April 2012 with progressive onset diminution of vision of the left eye associated with retroorbital pain during eye movements. Ophthalmologic examination revealed left visual acuity at 2/10 with a normal fundus examination. The patient was treated with oral corticosteroid therapy (1 mg/kg/day for 2 weeks) for left retrobulbar optic neuritis with partial improvement. In July 2016, the patient presented paresthesia and muscle weakness of all four limbs. On admission, the neurological examination revealed tetra-
pararesis associated with errors in the sense of position of the big toes, exaggerated tendon reflexes to all four limbs with bilateral Babinski sign, and visual acuity of the left eye at 4/10. Spinal cord MRI showed a transverse cervical myelitis, hyperintense on T2-weighted images and extending from bulbo-spinal junction to C7, without gadolinium enhancement (Fig. 2). The brain MRI did not find any signal abnormalities. The CSF study was normal. Serological tests for syphilis, HIV, hepatitis C and hepatitis B were negative. Soluble anti-nuclear antigen antibodies, antinuclear antibodies, anti-dsDNA, anti-SSA, anti-SSB and anti-AQP4 were normal. Detection of anti-myelin oligodendrocyte glycoprotein (anti-MOG) antibodies was not done. The search for pulmonary and extrapulmonary tuberculosis was negative. The diagnosis of NMOSD without AQP4-IgG was retained, and the patient was treated with pulse intravenous methylprednisolone (1 g/day for 3 days). Azathiorprine has been initiated as long-term treatment.
4.3.
Case no86
A 37-year-old woman, of Touareg origin, with no known past medical history, presented in July 2015 with rapidly progressive bilateral blindness over two days, not improved by the oral corticosteroid therapy (1 mg/kg/day for 2 weeks). In September 2017, the patient presented weakness of all four limbs associated with a hiccup, five weeks before admission. The neurological examination found tetraparesis predominant in the lower limbs, errors in the sense of position of the big toes, and bilateral blindness with abolition of the photomotor reflex. Spinal cord MRI showed an extensive medullary lesion in hypersignal T2 affecting the area postrema, without gadolinium enhancement (Fig. 3). The brain MRI did not find any signal abnormalities. The CSF study revealed a white blood cell count at 11/m3, with glucose at 0.67 g/L and protein at 0.42 g/L, without presence of oligoclonal bands. Serological tests for syphilis, HIV, hepatitis C and hepatitis B were
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Fig. 2 – Spinal-cord MRI, T2-weighted images (A, B): patient 5. Hyperintense lesion of the cervical spinal cord extending from bulbo-spinal junction to C7.
Fig. 3 – Spinal-cord MRI, T2-weighted images (A, B): patient 6. Hyperintense lesions of the cervical spinal and area postrema.
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negative. The dosage of vitamin B12 and ACE was normal. Antinuclear antibodies, anti-dsDNA, anti-SSA, anti-SSB and anti-AQP4 were normal as well as the search for tuberculosis infection. The diagnosis of NMOSD without AQP4-IgG was retained. The patient was treated with pulse intravenous methylprednisolone (1 g/day for 5 days), with partial clinical improvement, and then azathiorprine was started as long-term treatment.
4.4.
Case no87
A 26-year-old man, of Zarma origin, with no known past medical history, consulted for weakness of all four limbs with urinary incontinence that had started 10 days before admission. The neurological examination found a flaccid quadriplegia associated with a cervical sensory level. Spinal cord MRI showed transverse cervical myelitis, hyperintense on T2weighted images and extending from C2 to C5, without gadolinium enhancement (Fig. 4). The brain MRI did not find any signal abnormalities. The CSF study was normal. AntiAQP4 antibodies were positive. Antinuclear antibodies, antidsDNA, anti-SSA, and anti-SSB were normal as well as the search for tuberculosis infection. The thyroid function tests including anti-TG antibodies, anti-TPO, anti-TSH receptor antibodies, TSH, T3 and T4 were normal. Serological tests for syphilis, HIV, hepatitis C and hepatitis B were negative. The dosage of vitamin B12 and ACE was normal. The diagnosis of NMOSD with AQP4-IgG was retained. The patient was treated with pulse intravenous methylpredniso-
lone (1 g/day for 10 days), without any clinical improvement. Azathiorprine was started as long-term treatment.
5.
Discussion
We report a case series of patients from Niger who had never left the country before, diagnosed with inflammatory demyelinating diseases of CNS over a period of 21 years (1996–2017). Three patients were diagnosed with MS and the four others with NMOSD. After ruling out other etiologies with similar clinical pictures, the diagnosis of MS had been considered in our three patients according to the revised criteria of McDonald 2010 [13]. With respect to the NMOSD, the diagnosis was considered according to the international consensus diagnostic criteria for NMOSD [14]. We did not find any case of ADEM in this study. Our case series suggests the rarity of inflammatory demyelinating diseases of CNS in Niger, and NMOSD seems to be more frequent than MS. This higher susceptibility to NMOSD than to MS among sub-Saharan Africans has been reported previously by several authors [1,8–10]. In 2009, a Cuban study showed that the prevalence of NMOSD is higher among Afro-Cubans (0.69/100,000 inhabitants) than among Hispano-Cubans (0.42/100,000 inhabitants) [15]. In the French West Indies, populations mainly consituted by people of subSaharan African descent, a high prevalence of NMOSD (10/ 100,000 inhabitants) has been reported, suggesting a high susceptibility of people of sub-Saharan African descent to the NMOSD [16]. However, in 2012, an American multicenter study
Fig. 4 – Spinal-cord MRI, T2-weighted images (A, B): patient 7. Hyperintense lesion of the cervical spinal cord extending from C2 to C5.
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did not show this predominance of NMOSD among Americans of sub-Saharan African descent compared to white Americans [17]. The susceptibility of sub-Saharan Africans to the NMOSD could be due to the existence of environmental factors predisposing to NMOSD in SSA. Several microorganisms, which are common in SSA, have been reported in patients with NMOSD, among which the most frequently reported were mycobacterium tuberculosis, HIV, HTLV1, HHV, VZV, EBV, CMV [18]. Exposure to these microorganisms activates T and B cells. Activation of B cells produces antibodies directed against microorganisms, which interact by cross reaction with AQP4 causing injuries of tissues with high expression in AQP4 [19]. Genetic factors predisposing to NMOSD have also been reported. The genetic factor most extensively studied is the HLA. Blanco et al. [20] demonstrated that the frequency of HLA-DRB1*03 allele is significantly higher in patients with NMOSD than in healthy controls. Thus, studies had shown a high frequency of HLA-DRB1*03 allele in French Afro-Caribbean and Afro-Brazilian patients with NMOSD [21,22]. This genetic factor could also explain the susceptibility of subSaharan Africans to NMOSD. The low prevalence of MS among sub-Saharan Africans links to the existence of protective environmental factors against the risk of MS in tropical regions. The high levels of exposure to ultraviolet radiations in the tropical regions represent the most important protective environmental factor [23–25]. Ultraviolet radiations reduce the risk of MS by inducing the production of vitamin D3 in the cutaneous cells. Vitamin D3 induces a decrease of Th1 lymphocytes response, thus suppressing the increased production of interferon g, IL2 and TNFa which have a pro-inflammatory activity, and favors the Th2 lymphocytes response that produce IL4, IL5, IL6, IL10 and IL13 which have an anti-inflammatory activity and therefore a reduction of the risk of MS [26,27]. Intestinal parasitosis (helminthiasis, schistosomiasis, ascariasis, etc.) and some bacteria (Prevotella, Ruminococcus, Helicobacter pylori, some mycobacteria, etc.) represent the second protective environmental factor against MS [28–30]. Exposure to these microorganisms induces decreased activity of the immune system by activation of Th2 lymphocyte response [29,30]. In addition, helminth infection activates CD4CD25(+) FOXP3(+) T cells that induce Th2 lymphocytes response by suppressing Th1 lymphocyte response [31]. The unequal distribution of the prevalence of MS between different social groups in the same population, exposed to the same environmental factors suggests the implication of genetic factors in the pathogenesis of MS [7]. Thus, studies have shown that the prevalence of MS is lower among AfricoAmericans compared to white Americans [32,33]. In addition, Bhigjee et al. [34] showed in 2007 in South Africa a higher prevalence of MS among white South Africans compared to blacks. These data suggest the low risk of MS in black people.
6.
Conclusion
Our case series shows that inflammatory demyelinating diseases of CNS are rare in Niger, and NMOSD seems to be more frequent than MS. The prevalence and incidence of these diseases were unknown in Niger. A prospective epidemiological study in the
7
general population is needed to clarify the prevalence and incidence of MS and NMOSD in Nigerien populations.
Funding This study did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Disclosure of interest The authors declare that they have no competing interest.
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Please cite this article in press as: Assadeck H, et al. Inflammatory demyelinating diseases of the central nervous system in Niger. Revue neurologique (2018), https://doi.org/10.1016/j.neurol.2018.05.003