Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 29  |  Issue : 2  |  Page : 67-79

Neurofibromatosis and its Management in Nigeria: Important Neurologic and Neuro-ophthalmologic Considerations


Department of Ophthalmology, College of Medicine, University of Ibadan, Ibadan; Department of Ophthalmology, University College Hospital, Ibadan, Nigeria

Date of Submission25-Jan-2021
Date of Acceptance10-Jul-2021
Date of Web Publication18-Jan-2022

Correspondence Address:
Olufunmilola A Ogun
Department of Ophthalmology, University College Hospital, Ibadan, Post Code: 200212
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njo.njo_10_21

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  Abstract 


Neurofibromatosis (NF) is a relatively common disease with multisystemic manifestation. It is incurable and may be associated with learning difficulties and tumors such as optic nerve gliomas, brain tumors, and malignant peripheral nerve sheath tumors. This review seeks to increase awareness among physicians, surgeons, and ophthalmologists of the prevalence and manifestations of NF in the Nigerian environment, consequently, improving recognition, facilitating early diagnosis, follow-up, and treatment of the disabling complications of this disorder. The databases of “MedLine/PubMed,” “African-Journals-On-Line (AJOL),” “Google scholar,” and “UpToDate” were searched using the keywords Von Recklinghausen disease, familial NF, schwannomatosis, vestibular schwannoma, acoustic neuroma, meningioma, classical NF, central NF, neurofibroma, and other synonyms for NF were mapped to the key phrases “Nigeria,” “neurological,” and “complications.” Relevant MeSH terms were used alone and in combination, adding Boolean operators and wildcards to broaden, restrict, and modify the search, as required. This scoping review describes the historical origins, classification, diagnostic criteria, and clinical presentation of the three major types of NF, with a focus on neurologic complications. Thereafter, it reviews the literature on NF in Nigeria (Nigerians), discussing the implications for ophthalmologists and suggesting guidelines for multidisciplinary team management and follow-up in light of current advances in NF research. Neurologic complications of NF include epilepsy, headaches, learning difficulties, cranial and peripheral neuropathies, and intracranial tumors. Screening, early recognition, long-term monitoring, and rehabilitation by a multidisciplinary team, is required to enhance the quality of life of patients with NF. There are currently very few published studies describing the neurologic complications of NF among Nigerians. However, Nigerian physicians, surgeons, and ophthalmologists should be aware that patients with NF may develop these neurologic complications and should seek to identify them early, in the management and follow-up of patients with NF.

Keywords: Lisch nodules, neurofibromatosis, optic nerve glioma, schwannomatosis, vestibular schwannoma


How to cite this article:
Ogun OA. Neurofibromatosis and its Management in Nigeria: Important Neurologic and Neuro-ophthalmologic Considerations. Niger J Ophthalmol 2021;29:67-79

How to cite this URL:
Ogun OA. Neurofibromatosis and its Management in Nigeria: Important Neurologic and Neuro-ophthalmologic Considerations. Niger J Ophthalmol [serial online] 2021 [cited 2022 May 22];29:67-79. Available from: http://www.nigerianjournalofophthalmology.com/text.asp?2021/29/2/67/335909




  Introduction Top


The neurofibromatoses (plural for neurofibromatosis, hereafter abbreviated, NF) are neurocristopathies, affecting multiple systems; with a predilection for the skin, eyes, nervous system, and the bones.[1] There are several categories of NF,[2] but three major types are now widely accepted, with specified criteria for diagnosis.[3],[4],[5] Neurofibromatosis type 1 (NF1) is the commonest inherited neurocutaneous disorder with a prevalence ranging from 1 in 2500 to 1 in 3000.[6] It demonstrates very high penetrance with extremely variable phenotypic expression. NF is a life-long disorder with its different manifestations occurring at different ages.[7],[8] Therefore, patients with NF can present to any medical specialty.[8] More importantly, patients may not be aware of the condition, and the consulting physician must attend to the telltale signs, with a high index of suspicion, in order not to miss the diagnosis and to recognize the significance of, seemingly, unrelated comorbidities. The earliest reports of NF in Nigeria, date back to the 1970s.[9],[10] As there have been several reports on the physical disabilities and cosmetic disfigurement caused by NF in Nigerian patients,[11],[12],[13],[14],[15] there is limited reporting on the neurologic and neuro-ophthalmic manifestation. This scoping review therefore seeks to remind ophthalmologists about this ubiquitous, yet sometimes, disabling neuro-ophthalmologic condition.


  Methods Top


The following keywords “neurofibromatosis,” “Von Recklinghausen’s disease,” “familial neurofibromatosis,” “Schwannomatosis,” “vestibular Schwannoma,” “acoustic neuroma,” “meningiomatosis,” “classical neurofibromatosis,” “central neurofibromatosis,” “neurofibroma,” “meningioma,” and other synonyms for NF were mapped to the key phrases “Nigeria,” “neurological,” and “complication”. The databases of “MedLine/PubMed,” “African-Journals-On-Line (AJOL),” “Google scholar,” and “UpToDate” were searched using the keywords and related MeSH terms alone and in combination, adding Boolean operators and wildcards to broaden, restrict, and modify the search, as required. Other relevant sources were obtained from the reference lists of full text journal articles, if they had not already been identified, using the above search strategy, in any of the listed databases, but were cited within the article. All articles with full texts and abstracts in English language were included. Articles without accessible full texts and in which there was also no detailed abstract, as well as articles not in English language, which did not also have an English abstract, were excluded. All included full texts and abstracts were retrieved and reviewed to obtain information on the historical background, classification, genetics, pathogenesis, and clinical presentation including ophthalmologic manifestation, guidelines for diagnosis, clinical course, and neurologic and neuro-ophthalmologic complications; focusing on reports from Nigeria, as well as, guidelines on current therapies, management, follow-up and advances in molecular genetics, and relevant biomedical research for the future. Primary sources were original research articles published in peer-reviewed journals, and secondary sources were review articles, textbook chapters, websites, and online multimedia.


  Results Top


The PubMed search yielded 30 articles relating to NF in Nigeria, of which 23 articles were selected. Four articles were excluded upon reading the full text and identifying that the articles were not directly related to NF. Three articles were excluded due to lack of abstract or full text and no clear indication from their titles, which related to NF. A search for complications of NF in Nigeria yielded 13 articles on PubMed, of which search for articles specifically relating to neurologic complications of NF in Nigeria, yielded 19 hits on AJOL and 13 on GoogleScholar, of which 10 were eventually selected for this review. Other references, not specifically limited to Nigeria, were included for the purpose of introducing the topic and contextualizing the discussion.


  Discussion Top


Historical background

Robert Smith (1849), in Dublin, first described the classical signs of NF in 1849.[16] However, it was Friedrich Daniel Von Recklinghausen, a German pathologist, in 1882 who introduced the term “neurofibroma”; describing the benign peripheral nerve sheath tumor, that characterizes the disease that now bears his name.[17],[18] The NF is a genetically inherited autosomal-dominant disorder in which neural tissue develops benign tumors called neurofibromas, which may cause serious damage by compressing adjacent tissues. Although there are many variants of NF,[2],[19] three main classes of NF, namely type 1 (NF1 or classical NF), type 2 (NF2 or central NF), and type 3 (NF3 or peripheral schwannomatosis), are now accepted, based on molecular genetics and clinicopathologic characteristics.[5],[6],[20]

Neurofibromatosis 1

The NF1 has been identified worldwide,[2],[6],[7],[21],[22],[23],[24],[25],[26] including all major ethnic groups in Nigeria.[11],[12],[13] It is also called Von Recklinghausen disease, peripheral NF, or classic NF, and is the most common form of NF, accounting for up to 90% of cases. It is characterized by progressive appearance and growth of cutaneous nodules, focal areas of hyperpigmentation and hypopigmentation, called café au laît spots (also known as, café au laît macules or CALMs),[6] Lisch nodules on the iris, and a predisposition to central nervous system gliomas.[32] It is incurable, and may be associated with learning difficulties[33] and an increased lifetime risk of malignancy,[18] which may reduce life expectancy by 10 to 15 years, more so in females than in males.[34],[35] NF1 has a prevalence of 1 in 2000 to 4000 live births,[6],[7],[17],[18],[26] making it approximately 20 times more prevalent than NF2.[6] As approximately 50% of patients have a positive family history, the other 50% are sporadic, representing a new mutation.[6],[7],[17],[18] The National Institutes of Health (NIH) Consensus Development Conference formulated the diagnostic criteria for NF1 in 1987, which have since been used to make a clinical diagnosis of NF1.[3],[4] The NIH diagnostic criteria are listed in [Table 1]. The presence of any two of the listed criteria, in an individual, is required for diagnosis.[3],[4] These diagnostic criteria are robust and have stood the test of time.[7] It is noteworthy, however, that individuals with mosaic/segmental NF1 also fulfill the diagnostic criteria as they too present with the physical manifestations, only that these skin manifestations are usually restricted to a segment of the body.[6],[7] In segmental or mosaic NF, the lesion may be limited to a dermatome and not cross the midline, or involve a quadrant, half, or both sides, of the body.[6],[17] Half of patients with NF1 have cutaneous stigmata alone.[37]
Table 1 NIH diagnostic criteria for neurofibromatosis types 1 and 2[36]

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Neurofibromatosis 2

NF2 was first described by Wishart in 1822.[38] He described the clinical history and postmortem findings in a 21-year-old male, with multiple skull, brain, and nerve sheath tumors, unilateral blindness, and bilateral deafness. At the time, no reference was made to NF. Cushing in 1916 drew the parallel between NF and bilateral acoustic neuroma.[39],[40] The Manchester (modified NIH) diagnostic criteria for NF2 were proposed in 1990.[41] The modified NIH diagnostic criteria for NF2 are listed in [Table 2]. Prevalence of NF2 is estimated at approximately 1 in 50,000.[8],[39] Like NF1, NF2 is autosomal dominant in inheritance, with 50% to 60% occurring sporadically. In addition, NF2 runs a highly variable clinical course, with a high incidence of mosaicism.[39],[43] The severest form (Wishart type) manifests early with multiple clinical tumors and a severe disease course,[38] whereas the milder Gardner type[44] may remain localized and relatively asymptomatic throughout life.[39],[43] The hallmark of NF2 is the development of bilateral vestibular schwannomas (VSs).[40],[41],[44],[45] In addition, patients are prone to schwannomas of other cranial, spinal, and peripheral nerves; intracranial, intraspinal, and optic nerve sheath meningiomas as well as other low-grade gliomas, for example, ependymomas.[39],[45],[46] There are reports of NF2 from South Africa.[47],[48] However, there appears to be only one published report of NF2 from Nigeria.[49] This may be related to the paucity of neuroimaging and lack of genetic testing in most parts of Nigeria.
Table 2 NIH diagnostic criteria for neurofibromatosis type 2 modified from Evans et al.[42]

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Neurofibromatosis 3

The NF3 is the least common of the three major types of NF. The prevalence of NF3 ranges from 1 in 40,000 to 1 in 70,000.[50] It was first described, by Nimura, in 1973.[51],[52] It is characterized by the development of multiple benign tumors originating from Schwann cells (schwannomas) on cranial, spinal, and peripheral nerves.[52] Schwannomatosis should be suspected in any patient with multiple painful progressive swellings in the body, without the characteristic features of NF1 and NF2.[52] Schwannomatosis is primarily sporadic and inherited (i.e., familial) schwannomatosis is very rare.[52],[53] It most frequently presents between the third and sixth decade but there is no age or sex predilection in its occurrence. The main clinical presentation and indication for surgical excision is pain.[5] Because of the clinical overlap in the presentation of schwannomatosis and NF2, the diagnosis of NF3 is only made following detailed clinical and neuroradiologic evaluation of the skull base, to exclude diagnostic features of NF2, such as VS.[5] Diagnostic criteria for schwannomatosis have been proposed by Maccollin and colleagues.[5] It is not clear whether this has reached worldwide acceptance as the consensus. Nevertheless, there is no report, in literature, of NF3 in African or Nigerian patients [Table 3].
Table 3 Diagnostic criteria for neurofibromatosis type 3 (schwannomatosis) from Maccollin et al.[5]]

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Genetics of neurofibromatosis

The NF1 gene, a tumor suppressor gene, was cloned in 1990 and is located on chromosome 17q11.2.[54] It encodes the protein, neurofibromin, which is widely expressed in the nervous system. Loss of neurofibromin from mutation predisposes to increased risk of benign cutaneous, intraneural, and plexiform neurofibromas as well as malignant peripheral nerve sheath tumors (MPNSTs), in affected individuals.[54] Approximately half of cases arise from new germ-line mutations. The NF1 gene mutation is found in approximately 85% to 95% of patients with NF1.[7] Clinical manifestations of NF1 develop when the second copy of the NF1 gene is inactivated by a somatic mutation, according to Knudson two-hit theory.[54] Loss of heterozygosity resulting from deletion or pathogenic mutation of the remaining functional copy of the NF1 gene is a key early step in the development of benign and malignant neoplasms associated with NF. In vivo and in vitro studies show that Schwann cells lacking neurofibromin have a growth advantage over neurofibromin-positive ones, consistent with the infiltrative behaviors of plexiform neurofibromas and MPNSTs.[54] Simply put, patients with NF1 begin life with one functional copy and one mutated, nonfunctional copy of the NF1 gene. Random somatic inactivation of the remaining functional NF1 gene, results in complete loss of neurofibromin expression, is associated with tumor formation.[55] Conversely, haploinsufficiency may account for the neurocognitive problems, commonly associated with NF1.[17]

The gene locus for NF2 is located on chromosome 22 q.11.1-13[56] and represents a de novo pathogenic mutation in 50% to 60% of individuals, as such; there will be no family history in these cases.[18],[39],[57],[58] Members of the same family tend to have a similar severity of disease but disease severity differs between families.[43] This gene encodes for merlin (also known as neurofibromin 2 or Schwannomin); a cytoskeletal protein expressed mainly in Schwann cells, meningeal cells, lens fiber cells, and nerve cells, in adult life.[43]

Schwannomatosis or NF3 is characterized by germ-line or somatic mutations in LZTR1[50] and SMARCB1[59] genes resulting in slow-growing schwannomas of the cranial, spinal, and peripheral nerves.[50],[51],[52] Germ-line mutations of either the SMARCB1 or LZTR1 tumor suppressor genes have been identified in 86% of familial and 40% of patients with sporadic schwannomatosis.[50] Genetic cohort studies suggest that germ-line SMARCB1 mutations are present in at least 48% of familial and 9.8% of sporadic schwannomatosis cases.[50] Clinical features overlap with NF2 and may be indistinguishable without genetic testing.[5],[50],[51]

Pathogenesis

Neurofibromin is a negative regulator of ras kinase pathway.[54],[55] NF alters or weakens this protein structure due to gene deletion from missense or nonsense mutations. This allows rapid growth of cells all over the body especially around the nervous system. Increase in ras kinase activity, resulting from neurofibromin loss, activates key signaling cascades, which mediate mitogenesis, migration, and transformation of Schwann cells.[54]

The pathogenesis of NF2 is not entirely clear, loss of merlin leads to dysregulation of MAPK and RAS signaling; presumably resulting in loss of contact-mediated growth inhibition, which may play a major role in the pathogenesis of NF2-associated tumors.[43]

Schwannomatosis is an example of a tumor predisposition syndrome caused by the concomitant mutational inactivation of two or more tumor suppressor genes (biallelic mutation of SMARCB1 and LZTR1, in this case).[50] The classical two-hit model of tumorigenesis is insufficient to account for schwannoma growth, in schwannomatosis as NF2 is also frequently inactivated in these tumors.[43] It is believed that the pathogenesis of schwannomatosis is associated with mutational deletion of a large region of chromosome 22q comprising not just SMARCB1, but also LZTR1 and NF2 genes. Although schwannomatosis, despite its clinical similarity to NF2, is not associated with a germ-line mutation of NF2 gene.[50] The exact pathway of tumor predisposition is somewhat unclear.

Clinical presentation

Patients with NF have a highly variable clinical presentation and can present to any medical specialty clinic. The clinical manifestation of NF depends on the type of NF.

Neurofibromatosis type 1

Majority of cases may remain clinically asymptomatic and go undiagnosed. Diagnosis may be purely incidental, at the time of presentation for a totally unrelated complaint. The attention of an observant clinician may be drawn to the presence of multiple characteristic pigmented and depigmented macular skin lesions (CALMs) or presence of recognizable cutaneous or subcutaneous neurofibroma nodules.[6],[7],[8] Other manifestations with insidious onset include cognitive impairment, learning disabilities, and visual loss from amblyopia or optic pathway glioma.[60],[61],[62],[63] However, more dramatic clinical presentations may be associated with infiltrative or rapidly progressive tumors such as plexiform neuromas or MPNST.[64],[65] Although NF does not appear to increase the predisposition,[7] compared with the general population, NF does increase the risk of poor outcome in childhood myelocytic leukemia.[19] NF1 has also been described in association with other autoimmune systemic diseases such as multiple sclerosis[7],[18],[19],[21] and endocrine tumors.[7],[18],[19],[48] It is therefore important to examine all systems carefully, noting neurologic deficits, hypertension, and other systemic symptoms and signs[1],[2],[7],[14],[17],[18],[19] Ophthalmic evaluation should be performed to identify stigmata of NF, most importantly iris examination for Lisch nodules.[26],[61] Lisch nodules are melanocytic hamartomas, usually clear yellow to brown, that appear as well-defined, dome-shaped elevations projecting from the surface of the iris. Lisch nodules may be observed with or without magnification, but a slit lamp examination may be necessary to differentiate Lisch nodules from other iris lesions such as iris nevi.[61],[68],[69],[70] Lisch nodules are generally absent in central NF (NF2).[47] Usually arising in the first decade, virtually all patients with NF1 will have Lisch nodules by age 20 years.[17],[22],[28],[61],[69],[70],[71] Lisch nodules and other neurocutaneous manifestations of NF1 are shown in [Figure 1]. Plexiform neurofibromas of the eyelid usually present as thickening of the upper eyelid, with s-shaped deformity of the lid margin, feeling like a “bag-of-worms” on palpation. Congenital glaucoma ipsilateral to the plexiform neurofibromas has been described as a variation of anterior segment developmental disorders.[7],[18],[26],[61],[68],[71] Plexiform neurofibromas may arise from or extend into the orbit and may be associated with sphenoid dysplasia, presenting as proptosis.[26],[61],[71],[72],[73],[74] An example of sphenoid dysplasia and other forms of bony abnormalities in NF1 is shown in [Figure 2].
Figure 1 Neurocutaneous manifestations of neurofibromatosis 1. (a) Pediatrics 2008;121;633. (b) From Oheagbulam S. “Congenital” plexiform neurofibroma of the occipital scalp. Case report. JNS 1977;46:245-7. (c) Color  Atlas More Details of Pediatric Dermatology Samuel Weinberg, Neil S. Prose, Leonard Kristal Copyright 2008 by the McGraw-Hill Companies. www.medicinenet.com. Accessed January 24, 2021. (d) Café au laît macule from www.dermatologyadvisror.com. Accessed January 24, 2021. (e) Lisch nodules from https://webeye.ophth.uiowa.edu/eyeforum/atlas/pages/Lisch/index.htm. Accessed January 24, 2021. (f) From Adeleye et al. Cerebral pleomorphic xanthoastrocytoma associated with NF1: an updated review with a rare atypical case from Africa. Neurosurg Rev 2011;35:313-9. (g) Photograph taken by author, Ogun.

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Figure 2 Blue arrows depict bone dysplasia in an Axial Non-contrast Cranial CT of a patient with NF1, showing thinning of the right temporal bone and a defect in the occipital bone Blue star depicts sphenoid dysplasia with a defect in the greater wing of the sphenoid bone (posterior part of orbital roof). Adapted from Akinmoladun & Micheal (JMBR 2016).73

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Neurofibromatosis type 2

Patients present with distinctive cutaneous schwannomas, ophthalmologic findings, or neurologic deficits such as hearing loss or peripheral neuropathies, which may prompt further radiologic evaluation or, where available, genetic testing.[43] The distinctive cutaneous feature of NF2 is the “plaque-like” cutaneous schwannoma.[39],[43] These plaques are well-circumscribed, raised, and usually measuring less than 2 cm in diameter, with a rough surface, which may be slightly pigmented and frequently hairy.[39],[43],[58] Multiple CALMs are unusual and skin-fold freckling is not observed in NF2. Cutaneous NF occurs only in one out of four patients and tends to be fewer in number than is the case with NF1.[18],[39],[43] Lisch nodules are not reported; however, 75% of cases have cataracts, retinal harmatomas, and epiretinal membranes.[5],[75] Cataracts are often presenile posterior subcapsular cataracts or wedge-shaped cortical opacities.[26] Optic nerve astrocytic hamartomas, optic nerve sheath meningiomas, as well as combined hamartomas of the retina and retinal pigment epithelium are the most serious ocular manifestations of NF2 with potential for visual loss.[26],[46],[58],[75] In 60% of cases, VS [Figure 3] presents with insidious onset of profound unilateral or bilateral hearing loss in a young adult.[39],[47] Accompanying signs include: tinnitus, dizziness, and imbalance.[58] The severity is inversely proportional to the age of presentation, with younger age, predicting more severe disease.[58] Childhood presentation of meningioma or spinal tumor is highly suspicious for NF2.[39],[43],[76] Magnetic resonance imaging (MRI) of the skull base is used to identify VS and is superior to computed tomography (CT) in its resolution and sensitivity [Figure 4].
Figure 3 Small white arrows depict bilateral acoustic neuromas on Axial T1-weighted contrast-enhanced MRI in a patient with NF2. Adapted from Meola & Chang (NEJM 2018) Blue (left) and Red (right) arrows depict erosion and widening of the left and right internal acoustic canals respectively. From Radiopedia.org [accessed 15/09/2020].

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Figure 4 All red and green arrows refer to the unilateral vestibular Schwannoma in the CT and MRI images of 2 patients with NF2, showing the different enhancement patterns with the different radiological imaging techniques. From Radiopedia.org [accessed 15/09/2020].

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Schwannomatosis, NF3

Patients present with schwannomas on spinal roots, cranial nerves, plexuses, and peripheral nerves without VSs or cutaneous and ophthalmologic stigmata of NF1 or NF2. A formal ophthalmologic examination by an experienced ophthalmologist, as well as, the radiologic means of excluding VS, must be clearly documented, to avoid misdiagnosis of NF2 as scwannomatosis.[5],[76] The schwannomas are often subcutaneous and not attached to overlying skin (subdermal),[77] unlike neurofibromas.[5] Development of the schwannomas may be attributed to mild trauma and they tend to increase during pregnancy.[77] “Shooting” pain is often the most prominent clinical manifestation of schwannomas.[5],[52],[53],[77] Although there may be some asymptomatic spinal root schwannomas, the tumors located on spinal roots tend to cause weakness and dysesthesia in addition to pain, as a result of spinal cord compression.[77] Resection should be reserved for tumors that are symptomatic or threaten to cause spinal cord compression.[53]

Clinical course, neurologic complications including guidelines for management and follow-up

Overall morbidity and mortality of NF2 far exceeds that of NF1 because of neurologic complications.[6],[25] Morbidity is often a consequence of intracranial and other related tumors. Mortalityis, however, due to malignant transformation of tumors, which occur in about 3% of cases especially in NF2.[6],[25] VSs, associated with NF2, may have a higher risk of malignant progression following radiation therapy. Surgery remains the mainstay of management of VSs and peripheral schwannomatosis.

Neurologic complications

Créange described the neurologic manifestations of NF1 in a hospital-based series of 158 patients, which included 20 children, aged below 18 years.[6],[25] Fifty-five percent of all cases (87 out of 158) had at least one neurologic manifestation. Neuroimaging (CT or MRI scan) was performed in at least 87.4% of cases. Some patients had multiple neurologic complaints. In his analysis, Créange divided cases by age, into adults and children; and separated the neurologic disorders into anatomical categories based on the presence or absence of tumors: neoplastic tumors were categorized based on tumor location, whereas non-neoplastic complications were divided by region of the nervous system involved, into brain, spinal cord, peripheral nerve or cranial nerve involvement, and miscellaneous (pain) groups. Common non-neoplastic complications were headache, miscellaneous pain, hydrocephalus, seizures (epilepsy), and migraine. On the other hand, the commonest tumors were: optic pathway tumors, MPNSTs, gliomas, and cerebral meningiomas. Cranial nerve involvement was rare, and mostly affected the facial nerve. With respect to the age of onset, symptomatic and asymptomatic optic pathway tumors had the earliest age at presentation, whereas meningiomas had the latest age at presentation [Figure 5]. In comparison to other studies, headache, hydrocephalus, seizures, and brain tumors were the most consistent neurologic complications found[25] [Table 4].
Figure 5 Neurologic manifestations of neurofibromatosis 1 according to age at presentation or discovery, and severity of symptoms from Créange et al.[25] MPNST, malignant peripheral nerve sheath tumor; OPT, optic pathway tumor. ● Asymptomatic and/or severe manifestation.

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Table 4 Summary of isolated case reports describing neurofibromatosis in Nigerian patients

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Clinical course of optic pathway tumors

Optic pathway tumors showed greater progression and were often diagnosed, in childhood. When diagnosed in adulthood, optic pathway tumors showed little visual compromise, even if demonstrating radiologic progression when followed up for over 10 years.[25]

Malignant peripheral nerve sheath tumors

These tumors were diagnosed, in adults and children, between the second and third decades of life and frequently presented as rapid increase in growth of a pre-existing subcutaneous NF, causing pain or neurologic (motor) deficit. Most cases of MPNST resulted in death within 5 years despite extensive or repeated surgeries. And only one patient out of a total of five cases of MPNST remained alive, up to 2 years following limb amputation for MPNST.[25]

Clinical course of epilepsy

Epilepsy was often related to the presence of cerebral harmatomas, acqueductal stenosis, meningioma, or posttraumatic subdural hematoma.[25] The seizures ran a relatively benign course with most cases responding to monotherapy. Clinically, majority of patients presented with generalized seizures but the patient with a harmatoma, presented with complex partial seizures.[25] Seizures in NF2 may be a presenting sign in meningioma or meningiomatosis.[43] However, intractable epilepsy, resistant to treatment is associated with severe mental retardation.[86],[87]

Spinal compression and peripheral neuropathy

In NF1, spinal compression is often a result of benign intraspinal NF in a child or adult, or intraspinal extension of MPNST in adults.[25] In NF2 and schwannomatosis, tiny nerve root schwannomas may present with respective motor weakness and sensory symptoms. In NF2, nerve compression produces mononeuropathy in childhood and polyneuropathy in adulthood.[43] Depending on the location of an intraspinal NF, NF1 patients may present with paraparesis, paraplegia, quadriparesis, or quadriplegia or cauda equine syndromes accompanied by sphincteric dysfunction.[25] Spinal compression from MPNST in NF1 is accompanied by pain.[25]

Headache and other pains

Although headaches were very common among patients with NF1, they were controllable in the majority of cases with analgesics, antidepressants, anticonvulsants, or combinations of these.[25] Severe migraine was very rare, occurring in only two cases. Surgical intervention for pain such as (spinal root section and anterolateral cordectomy) was reserved for pain related to MPNST.[25] Headache in NF2 is related to the development of meningiomatosis.[43] Intractable peripheral pain (nonheadache associated pain) is often the presenting symptom in NF3.[43],[52],[76]

Hydrocephalus and cerebral glioma

All symptomatic cases of hydrocephalus occurred in children. Hydrocephalus, for the most part, seems related to compression or aqueductal stenosis from a progressive optic pathway or intracerebral neoplasm. Growth of these tumors, especially in adults, is too insidious to warrant serial neuroimaging.[25]

Schwannomatosis, meningiomatosis, and ependymomas

Schwannomas are common in NF2 and NF3. Schwannomas in NF2 tend to present early in childhood or young adulthood and are often associated with neurologic deficits such as weakness or sensory loss, whereas schwannomas associated with NF3 have a much later presentation, being diagnosed later in life and more frequently associated with pain.[43],[52],[77]

The schwannomas of NF2 are of the plexiform type involving multiple nerves roots in the cervical region, brachial plexus, and sacral plexus, as well as the distinctive intradermal plaque lesion and unilateral or bilateral VSs.[43] The schwannomas of NF2 show positive vascular endothelial growth factor staining on immunohistochemistry and treatment with Bevacizumab has been reported to cause reduction in tumor size and improved hearing, in some cases of VS. [43],[88] Schwannomas in NF2, if irradiated, may show transformation to MPNST. [43]

Management and follow-up

Annual follow-up with a full ophthalmologic examination (including visual acuity, color vision, visual fields, and slit-lamp examination) can be adopted in children and adults in lieu of serial neuroimaging in the asymptomatic patient with stigmata of NF. [Table 5] provides suggested guidelines for follow-up of Nigerian patients with NF, inspired by recently published French national guidelines,[6] in addition to published literature on NF in Nigeria.
Table 5 Suggested screening guidelines for the presence of neurologic complications, in individuals with NF[6]]

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Neurofibromatosis in Nigeria

The first report of NF in a Nigerian was published by Oheagbulam in 1977.[10] He described the presentation of a 13-year-old female with a left occipital scalp mass that had slowly increased in size from 1 month of age. The patient had remained otherwise asymptomatic and had presented mostly for cosmetic reasons. Histology confirmed a plexiform neurofibroma, skull X-ray showed an underlying occipital bony defect, and patient remained stable for the 18-month follow-up period postoperatively.[10] The first Nigerian case series was reported by Ademiluyi and Ijaduola, in a 6-year prospective, clinicopathologic study on 14 children with NF at Lagos University Teaching Hospital between 1979 and 1985. No ocular lesion was reported in their series. This may have been due to low awareness, failure to obtain formal ophthalmologic evaluation, or simply the young age of their patients (age range 3 months to 14 years) with a mean age of 4 years.[11] Though Lisch nodules have been identified in children as young as 3 years of age, prevalence is only 33% to 50% between the ages of 2.5 and 5 years, respectively.[68] The largest Nigerian study to date was published by Odebode et al. in a 20-year retrospective review of 98 histologically diagnosed cases of NF1, between 1980 and 2001, at the University of Ilorin Teaching Hospital.[15] In this series, iris Lisch nodules, which were the only ocular lesion reported in three out of only five patients, examined by an ophthalmologist.[15] It is expected that the range of ophthalmologic manifestations would have been more diverse had all patients, or at least majority of cases, received an ophthalmologic review. More so, only 1 out of the 98 patients had neuroimaging.[15] Nyandaiti et al. described 47 cases from North-East Nigeria, majority of their cases had CALMs, axillary freckling, and plexiform neurofibromas, and there was a positive family history of NF1 in about a third of cases (16 cases).[14] Interestingly, axillary and groin freckling was much more common than was observed by Ademiluyi and Ijaduola,[11] Odebode et al.,[15] or Azeke and Imasogie.[13] However, none of the cases had neuroimaging, cognitive assessment, or ophthalmologic examination. Therefore, there was no record of neurologic or ophthalmologic complications.[14] Azeke and Imasogie in Benin, Edo state, conducted a review of histologic samples collected over a 10-year period and diagnosed neurofibromas in 46 out of 188 samples (24%).[13] Most samples were from the head and neck regions, but none of the cases had neuroimaging or ophthalmologic examination either.[13] Asuquo et al. in Calabar, published a case series of three patients with MPNST; two of whom had NF1 and were up to 20 years younger than the case that was not associated with NF.[12] Likewise, none of the cases had ophthalmologic assessment or neuroimaging.[12] Both MPNSTs had arisen within a pre-existing plexiform neurofibroma, supporting suspicions of the long-term malignant potential of plexiform neurofibromas. [23]

Recently, Ogun et al.[89] conducted a 10-year retrospective audit of clinical, pathologic, and ophthalmologic manifestations of NF, in Nigerians (submitted for publication). All 34 patients had NF1 and were examined by an ophthalmologist. Neuroimaging was performed in six (17.6%) of cases and afforded the diagnosis of neuro-ophthalmologic manifestations. Lisch nodules were the most common ocular manifestation, although most patients presented because of plexiform tumors of the lid and craniofacial region. Three cases were diagnosed with optic pathway gliomas, one of which was malignant. One case had presented to the ophthalmologist with retinal detachment, whereas unaware of, and asymptomatic for, a concurrent, huge intracranial intraventricular mass, with hydrocephalus.[82],[89] Ohaegbulam reviewed 612 intracranial tumors in a 13-year period (January 2003–December 2015) and found only 3 cases of VS (0.49%), of which only 1 was related to NF. The single case of NF2 reported in a Nigerian was a 28-year-old male with a 2-year history of seizures, bilateral vision loss, and bilateral deafness. The diagnosis of NF2 was based on the histology and radiologic evidence of bilateral VS. There was no report of an ophthalmologic review and there was no family history.[49] Though VS is also known to occur alone, according to the NIH diagnostic criteria, individuals with unilateral VS, may also be diagnosed with NF2, in the presence of any two additional criteria, as listed in [Table 2]. However, the authors did not specify in their article, how the other criteria for NF2 were excluded in the remaining two cases of unilateral VS.[49]

Finally, the remaining literature on NF in Nigeria comprises unrelated case reports of patients with interesting clinical presentations in different parts of Nigeria. These are summarized as a literature matrix in [Table 4]. All cases had NF1, there are no reports of NF2 or schwannomatosis in Nigeria or Nigerian patients. The case series from Lagos,[11] Benin,[13] Azare and Maiguguri,[14] had no neuroimaging at all[11] making the detection of optic pathway glioma or asymptomatic intracranial tumors less likely. Although long-term follow-up of asymptomatic intracerebral gliomas has demonstrated that they run a very slow and indolent course, which does not warrant routine serial neuroimaging.[25] Nevertheless, serial ophthalmologic assessment is required but was lacking in many Nigerian studies.


  Conclusion and Recommendations Top


The NF is a ubiquitous and protean disorder with potential to severely impact the growth, development, health and quality of life of patients and their families. More than 50% will develop neurologic complications at some point in the course of the disease. Nigerians tend to present late with severely disfiguring masses or MPNST, which can be fatal. Ophthalmologists play a pivotal role in the diagnosis and follow-up of patients with NF worldwide. However, Nigerian ophthalmologists are under-represented in the screening and follow-up of Nigerian patients with NF.

Screening for cognitive impairment and other neurologic complications is suboptimal in Nigeria; therefore, the importance of a multidisciplinary team approach cannot be overemphasized. Moreover, the diagnostic criteria for NF may be changing in the near future, to reflect current capabilities for genetic testing and recent advances in clinical research in the field, for example, optical coherence tomography criteria to further address overlap in clinical presentation. Therefore, Nigerian ophthalmologists must keep abreast of the progress in NF research to meet the critical challenges of early and accurate diagnosis, recommendations for follow-up, advances in therapeutic management, and rehabilitation to achieve the best quality of life for our patients.

Implications for ophthalmologists in Nigeria

Ophthalmologists in Nigeria should advocate more, for multidisciplinary management of patients with multisystem disorders, including NF, to provide the highest standard of health care within the capabilities of our available resources. Furthermore, in the case of NF, ophthalmologists should recognize and investigate all incidental cases of Lisch nodules and optic atrophy (optic nerve head pallor) or papilledema (optic nerve head swelling) for optic pathway gliomas in NF1 and optic nerve sheath meningioma or intracranial meningiomas in NF2. Benign retinal tumors or retinal harmatomas (retinal astrocytomas and retinal capillary hemangiomas) may be present in patients with NF2 and should not be missed. Finally, ophthalmologists need to recognize the existence of schwannomatosis (NF3) as a separate entity, despite the significant overlap with NF2 because the clinical course, follow-up, and prognosis are very different.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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