Idiopathic Intracranial Hypertension (IIH) in Diabetic mellitus
IIH (i.e., pseudotumor cerebri) is an idiopathic disorder characterized by symptoms, signs, and radiographic findings of elevated intracranial pressure (ICP) without an apparent etiology. A negative neuroimaging study (e.g., magnetic resonance imaging (MRI) with and without contrast and MR venography (MRV)) as well as normal cerebrospinal fluid (CSF) content is required for the diagnosis to meet modified Dandy criteria for IIH. This monograph reviews the unique challenges of IIH in patients with diabetes mellitus.
Diabetes mellitus (DM) is a disorder of insulin (production or response) that produces hyperglycemia. Chronic hyperglycemia leads to pericyte and endothelial cell damage that can produce ischemia in the retina resulting in non-proliferative and proliferative diabetic retinopathy (PDR). PDR is a late ocular complication of DM and is characterized by neovascularization (NV) of the optic disc (NVD), NV of the iris (NVI), and NV elsewhere (NVE) in the retina. PDR can lead to severe visual complications (e.g., tractional retinal detachment, vitreous hemorrhage, neovascular glaucoma). Vitreous hemorrhage (VH) is the result of the rupture of these abnormal NV blood vessels. PDR is due to retinal angiogenic factors (e.g., vascular endothelial growth factor (VEGF)) and intravitreal anti-VEGF therapy and laser therapy with panretinal photocoagulation may be necessary in PDR. The common risk factor for both IIH and DM is obesity and thus some patients have both conditions. The modified Dandy criteria for IIH do not preclude the presence of co-morbidities like DM.
A study by Miah et al. found that the prevalence and incidence of IIH have increased significantly from 2003 to 2017. Their study showed that in 2017 the incidence and prevalence of IIH were 7.8 per 100,000 and 76 per 100,000, respectively. This is a significant increase from 2003, when the incidence and prevalence were recorded to be 2.3 per 100,000 and 12 per 100,000, respectively. Obesity (defined by a body mass index (BMI) > 30 kg/m2) is an important risk factor for IIH. The majority of IIH cases are obese women of childbearing age, and the incidence of IIH in obese women aged 15-44 years-old was 22.0 per 100,000. Furthermore, women compose ~90% of the patient population. Although there have been no specific directed studies to ascertain the exact incidence or prevalence of IIH in patients with DM, the co-association in obese patients may be under-recognized.
The etiology of IIH is not yet completely understood. Obesity is a highly associated risk factor with IIH, and increasing BMI leads to increased risk for IIH. It is important to also note that obesity commonly predisposes to diabetes. Moreover, the presence of other risk factors that predispose patients to both IIH and diabetes may conceivably lead to IIH in the setting of PDR with VH.
● Polycystic ovarian syndrome (PCOS)
● Obstructive sleep apnea (OSA)
● Systemic lupus erythematosus (SLE)
Interestingly, there may be a role between metabolism and IIH. Type 2 DM may lead to increased ICP, as Type 2 DM has been associated with increased ICP in rats. Furthermore, central adiposity may lead to greater risk for increased ICP than peripheral adiposity does.
The pathophysiology of IIH has not been completely understood, and there are multiple lines of thought. One theory suggests that mechanical effects of excessive central adiposity increase intra-abdominal pressure; this subsequently elevates intrathoracic pressure and may impede venous return from the brain. Intracranial venous pressure may rise and thereby lead to IIH. However, this theory does not support how IIH may arise in non-obese patients. Other theories suggest increased cerebrospinal fluid (CSF) production, decreased CSF drainage, or even vitamin A excess; no theory has been proven to sufficiently describe the pathophysiology of IIH.
However, it is interesting to note that distinct androgen levels have been found in the CSF of many IIH patients. Considering certain risk factors (e.g., PCOS), endocrine dysfunction may impact CSF secretion in IIH. Furthermore, glucagon like peptide-1 receptor (GLP-1R) agonists (e.g., exenatide) have been shown to lower elevated ICP in hydrocephalic rats.
Thus, endocrine dysfunction as well as metabolic dysregulation may play important roles in the pathogenesis of IIH. It is plausible that patients with impaired endocrine and/or metabolic function (e.g., systemic diabetes) develop IIH at least partially as a result of their endocrine or metabolic dysfunction. However, it is uncertain when and why IIH would develop in these patients. IIH may possibly develop in late stages (e.g., PDR with VH) or may occur earlier in the disease process, but more research is necessary to determine during which stages of endocrine/metabolic dysfunction are more vulnerable to developing IIH.
IIH sometimes occurs acutely (less than four weeks) and can produce visual acuity and/or visual field loss that is severe. This acute and severe form of IIH has been termed fulminant IIH. Acute VH related to PDR can mimic or mask fulminant IIH. It is important to differentiate the two etiologies (PDR versus fulminant IIIH) because the latter may require aggressive surgical intervention for vision threatening papilledema.
The modified Dandy criteria do not require papilledema to be present but the major cause of visual loss in IIH is papilledema. In contrast, the major causes of visual loss in DR are diabetic macular edema (DME) or VH in PDR. Severe VH however may preclude adequate visualization of underlying papilledema. In addition, some patients with diabetic papillitis can mimic papilledema. Thus, MRI of the head and orbit with contrast and MR venography (MRV) are recommended for patients with bilateral optic disc edema. Lumbar puncture should also be considered in such cases even when the diabetic papillitis is in the differential diagnosis. In cases with severe VH, orbital ultrasound can not only exclude underlying tractional or other retinal detachment but can also visualize papilledema. In patients with neuroimaging features of elevated ICP (e.g. flattening of the globe, fluid in the optic nerve sheath, empty sella, and venous sinus stenosis) a lumbar puncture may be necessary to confirm increased ICP. Another potential challenge in cases of IIH and DM is the presence of diabetic kidney disease. Impaired glomerular filtration rate (GFR) may preclude the use of gadolinium contrast in MRI.
In addition, although the modified Dandy criteria require normal CSF contents, CSF glucose levels may be elevated in diabetic patients and should be correlated with elevated serum glucose.
The treatment for fulminant IIH differs from that of typical IIH due to the high risk of irreversible vision loss and often requires surgery. For IIH patients with PDR and VH, it may also be necessary to undergo pars plana vitrectomy (PPV) to clear VH to improve visualization of the posterior pole and to diagnose and monitor papilledema. Surgical intervention may also be necessary for fulminant IIH.  While awaiting definitive surgical intervention, high-dose acetazolamide (2-4 g per day) may be administered as a temporizing measure. The surgical options include optic nerve sheath fenestrations, venous sinus stenting, and CSF shunting procedures. Bariatric surgery is also a potential option for treating IIH and DM in obese patients, as it may decrease elevated intra-abdominal pressure from central adiposity. Moreover, bariatric surgery may help IIH patients with PDR and VH attain better control of DM. This is because obese patients with type 2 DM who undergo bariatric surgery also have a concominat decrease in hemoglobin A1c; patients with the largest decrease in Hb A1c tend to have the best remission from diabetes. However, bariatric surgery only provides a more long-term option in the management of IIH in obese patients.
The prognosis of fulminant IIH greatly depends on its prompt recognition, diagnosis, and treatment. Furthermore, the risk for irreversible vision loss increases with increasing BMI, especially with BMI > 40 kg/m2. If immediate surgical intervention is performed, vision may be preserved and there may also be vision recovery. The potential for notable vision recovery greatly decreases over time without treatment.
IIH can occur in the setting of DM. Diabetic papillitis can mimic papilledema but neuroimaging and LP should be considered in such cases as DM is a diagnosis of exclusion in bilateral optic disc edema. Fulminant IIH occurs with rapid progression and severe vision loss and typically requires urgent surgical intervention. Acute visual loss can occur in PDR due to DME or VH and severe VH can obscure the view of the fundus. Neuroimaging to look for radiographic features of IIH may be helpful in such cases and orbital ultrasound can detect underlying disc edema even if the fundus view is obscured by VH. Earlier PPV may be necessary in cases of PDR with VH with suspected papilledema in order to provide a clear view of the fundus.
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