Intracranial Hypertension and Nephropathic Cystinosis in Monozygotic Twins

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Intracranial Hypertension and Nephropathic Cystinosis in Monozygotic Twins Danny A. Mammo, MD, Collin M. McClelland, MD, Michael S. Lee, MD I diopathic intracranial hypertension (IIH) is a condition most commonly found in reproductive age, obese women and is characterized by elevated intracranial pressure without an identified causative factor (1). A few reports describe familial clusters and cases among twins with IIH (1,2). Cystinosis is a rare autosomal recessive disorder characterized by elevated lysosomal cysteine deposition due to impaired lysosomal membrane transport. Nephropathic cystinosis leads to progressive renal failure requiring renal transplant and extrarenal manifestations including corneal crystal deposition. Rarely, cerebral involvement including IIH has been reported in association with cystinosis, with 11 total cases in the literature (3–6). The incidence of IIH and cystinosis occurring separately in the general population is 1.8 per 100,000 and w1 per 150,000, respectively. Therefore, the odds of cystinosis and IIH coincidentally occurring concurrently are approximately 1 in 10 billion (3). To the best of our knowledge, the occurrence of IIH and cystinosis in twins has not been reported. We describe 2 cases of nephropathic cystinosis and IIH in adult, female monozygotic twins of normal body mass index (BMI). A 33-year-old Caucasian woman with a history of nephropathic cystinosis status after a living-donor kidney transplant 3 years before presented with bilateral blurry vision. She endorsed new bifrontal, throbbing headaches. Her height was 59 199 , and her weight was 115 pounds (BMI 21.7). Her medications included oral and topical cysteamine, tacrolimus, and mycophenolic acid. Examination demonstrated bilateral corneal crystals and moderate optic disc edema and average retinal nerve fiber layer (RNFL) thicknesses of 170 mm right eye (RE) and 278 mm left eye (LE). The rest of her ophthalmologic examination including strabismus testing and automated 30-2 perimetry was unremarkable. She underwent normal brain MRI and magnetic resonance venography (MRV), and lumbar puncture (LP) in the lateral decubitus position showed an opening pressure (OP) of 31 cm H2O with normal cerebrospinal fluid (CSF) cell counts. She was managed with oral acetazolamide 500 mg twice daily. No weight loss was recommended given her thin body habitus. Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota. The authors report no conflicts of interest. Address correspondence to Michael S. Lee, MD, Department of Ophthalmology and Visual Neurosciences, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455; E-mail: mikelee@ umn.edu Mammo et al: J Neuro-Ophthalmol 2022; 42: e315-e317 She developed worsening kidney function and her transplant specialist discontinued acetazolamide. She subsequently developed binocular horizontal diplopia with worsening optic nerve edema (average optical coherence tomography [OCT] RNFL 196 mm RE, 311 mm LE). She underwent a ventriculoperitoneal shunt with resolution of her symptoms and papilledema (average RNFL 123 mm RE, 131 mm LE). At most recent follow-up, her visual acuities were 20/30 and 20/25 in the right and left eyes, respectively, with full color plates in each eye. Her automated 30-2 perimetry testing continued to show no deficits. The monozygotic twin of the patient above presented with bilateral blurry vision, headaches, and nausea at the age of 35 years in the setting of a normal body habitus (BMI 24.4) and history of nephropathic cystinosis status after a living-donor kidney transplant 16 months before. Her medications included oral and topical cysteamine, cyclosporine, and mycophenolic acid. Examination demonstrated bilateral corneal crystals and mild optic disc edema with Paton folds. Her automated 30-2 perimetry testing was normal, and the average OCT RNFL was 177 mm RE and 174 mm LE. She underwent normal brain MRI and MRV. Subsequent LP in the lateral decubitus position demonstrated an OP of 52 cm H2O and elevated CSF red blood cell count (314/mL), white blood cell count (white blood cell [WBC], 150/mL, 85% lymphocytes) elevated protein (88 mg/dL), and low glucose (47 mg/dL). She was afebrile, and her extensive meningitis evaluation was negative including CSF culture, gram stain, polymerase chain reaction for tick-borne illnesses, cytomegalovirus, Cryptococcus, Enterovirus, herpes simplex virus, HHV6, varicella zoster virus, Streptococcus, among others. Repeat LP 2 weeks later showed that the WBC came down to 74/mL. Her OP was 30 cm H2O. Her complete blood count showed a WBC of 5.1. Initially, she was believed to have viral meningitis. However, her papilledema persisted over the next 2 years, which was inconsistent with a transient optic nerve swelling from viral meningitis. Her diagnosis was changed to presumed IIH. Because of persistent headache, repeat LP 2 years after the initial presentation showed normal constituents and an OP of 8 cm H2O. At her last follow-up 2.5 years after presentation, her visual acuities were 20/30 RE and 20/20 LE. She was off acetazolamide without papilledema (mean RNFL thickness of 123 RE and 121 LE), and her visual fields remained normal. We present monozygotic twins with cystinosis who developed intracranial hypertension. Although the CSF of e315 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence Twin B initially showed findings consistent with infection, her slow improvement over 2 years in the absence of other signs or symptoms of meningitis argues for the diagnosis of presumed IIH. We acknowledge that Twin B may have a predisposition to IIH perhaps triggered by another process, but her clinical course was not consistent with infection. We reviewed the English literature for cases of IIH and cystinosis and found 11 other cases (Table 1), all of whom had nephropathic disease. Although it could be argued that these disorders are unrelated, the presence of IIH in monozygotic twins strongly supports an association. The exact pathophysiology of how IIH may occur in cystinosis patients is speculative. The prevalent theory is cystinosis accumulation in the arachnoid villi that blocks CSF resorption, as cystine deposition has been noted in the choroid plexus and brain parenchyma (3). Cystine accumulation has also been shown to increase the rate of apoptosis in renal proximal tubule epithelial cells, which suggests that apoptosis of arachnoid villi from cystine deposition may serve as another plausible mechanism for increased intracranial hypertension in these patients (3). Renal transplantation has been reported often as a risk factor for IIH and many nephropathic cystinosis patients require renal transplant. However, cases of cystinosis and IIH before renal transplantation have been reported which suggest that renal transplantation is not the cause of the association (3). It is possible that medications may have played a role in our TABLE 1. Clinical characteristics of patients concurrently diagnosed with idiopathic intracranial hypertension and cystinosis Patient Gender/Age (y) of IIH Onset 1* Male/14 Nephropathic 10 yrs, good compliance 2* Female/13 Nephropathic 3* Female/16 Nephropathic 4* Male/17 Nephropathic 5* Female/5 Nephropathic 6* Male/14 Nephropathic 7* Female/16 Nephropathic 8* Female/47 Nephropathic 11 yrs, poor compliance 13 yrs, poor compliance 16 yrs, good compliance 5 yrs, good compliance 13 yrs, good compliance 14 yrs, good compliance None 9† Male/11 Nephropathic 10‡ 11§ Male/16 Female/15 Nephropathic Nephropathic 12 (present study) 13 (present study, twin of patient 12) Female/36 Nephropathic Female/36 Nephropathic Cystinosis Type Cysteamine Intake? 5 yrs, good compliance Yes Yes Yes, good compliance Yes, good compliance Other Medications Associated With IIH Renal Transplant at Time of Diagnosis? Prednisone, cyclosporine, growth hormone Levothyroxine Yes Prednisone, cyclosporine Prednisone, cyclosporine Vitamin D Yes Yes None No Prednisone, levothyroxine Prednisone, cyclosporine, oral contraceptive pill Levothyroxine Yes No No Yes Yes Levothyroxine Prednisone, levothyroxine, vitamin D None No Yes Yes Cyclosporine Yes *Dogulu CF, Tsilou E, Rubin B, et al. Idiopathic intracranial hypertension in cystinosis. J Pediatr. 2004; 145(5):673–8. † Parnes A, Wassner SJ, Weinstein JM. A case of intracranial hypertension and papilledema associated with nephropathic cystinosis and ocular involvement. Binocul Vis Strabismus Q. 2008; 23(1):37–40. ‡ Sürmeli döen S, Delibaş A, Kayacan UR, Ünal S. Short-cut diagnostic tool in cystinosis: Bone marrow aspiration. Pediatr Int. 2017; 59(11):1178–1182. § Behdad B, agheri A, Tavakoli M, Pakravan M. Association of Nephropathic Cystinosis and Pseudotumor Cerebri with Bilateral Duane Syndrome Type I. Neuroophthalmology. 2014; 38(2):74–77. IIH, idiopathic intracranial hypertension. e316 Mammo et al: J Neuro-Ophthalmol 2022; 42: e315-e317 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence patients. Both patients were taking medications that have been implicated in IIH: Case 1 took tacrolimus (7) and mycophenolic acid (8) and Case 2 took cyclosporine (9) and mycophenolic acid (8). However, Case 2 did not stop her medications and the papilledema resolved. The largest series of familial IIH clusters suggests an autosomal dominant pattern of inheritance and most of the patients were obese; interestingly, the age of disease onset between family members tended to be similar and the role of a “genetic clock” has been suggested (2). Similarly, our twin patients were diagnosed with IIH around the same age, in their mid-30s. Unlike Corbett’s series, both of our patients showed a normal BMI. In summary, we report the rare association of IIH and nephropathic cystinosis and, to the best of our knowledge, the first report in monozygotic twins. REFERENCES 1. Stevens SM, McClelland CM, Chen JJ, Lee MS. Idiopathic intracranial hypertension in a mother and pre-pubertal twins. Neuroophthalmology. 2019;43:49–52. 2. Corbett J. The first Jacobsons Lecture. Familial idiopathic intracranial hypertension. J Neuroophthalmol. 2008;28:337– 347. Mammo et al: J Neuro-Ophthalmol 2022; 42: e315-e317 3. Dogulu CF, Tsilou E, Rubin B, Fitzgibbon EJ, Kaiser-Kupper MI, Rennert OM, Gahl WA. Idiopathic intracranial hypertension in cystinosis. J Pediatr. 2004;145:673–678. 4. Parnes A, Wassner SJ, Weinstein JM. A case of intracranial hypertension and papilledema associated with nephropathic cystinosis and ocular involvement. Binocul Vis Strabismus Q. 2008;23:37–40. 5. Sürmeli döven S, Delibaş A, Kayacan UR, Ünal S. Short-cut diagnostic tool in cystinosis: Bone marrow aspiration. Pediatr Int. 2017;59:1178–1182. 6. Behdad B, Bagheri A, Tavakoli M, Pakravan M. Association of nephropathic cystinosis and pseudotumor cerebri with bilateral duane syndrome type I. Neuroophthalmology. 2014;38:74–77. 7. Chamberlain CE, FitzGibbon E, Wassermann EM, Butman JA, Kettl D, Hale D, Kirk AD, Mannon RB. Idiopathic intracranial hypertension following kidney transplantation: a case report and review of the literature. Pediatr Transpl. 2005;9:545–550. 8. Patiroglu T, Ozcan A, Karakukcu M, Ozdemir MA, Poyrazoglu G, Canpolat M, Unal E. Mycophenolate mofetil-induced pseudotumor cerebri in a boy with autoimmune lymphoproliferative disease. Childs Nerv Syst. 2011;27:853– 855. 9. Morente GB, Sanchez JT, Colmenero CG, Garcia EM, MolinaCarballo A. Pseudotumor cerebri associated with cyclosporine use in severe atopic dermatitis. Pediatr Dermatol. 2015;32:237–239. e317 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.