Idiopathic Intracranial Hypertension following Levothyroxine Replacement Therapy: Systematic Review and a Case Report : Indian Journal of Endocrinology and Metabolism

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Idiopathic Intracranial Hypertension following Levothyroxine Replacement Therapy: Systematic Review and a Case Report

Datta, Sumanas G.1,2; S.L, Sagar Reddy1; Dhananjaya, Melkunte S.1; Tamminedi, Nitin1; Nayak, Vittal3; Kodapala, Suresha4; Sarathi, Vijaya1,

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Indian Journal of Endocrinology and Metabolism 27(1):p 17-24, Jan–Feb 2023. | DOI: 10.4103/ijem.ijem_439_22
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Idiopathic intracranial hypertension (IIH) is a disorder characterized by increased intracranial pressure of unknown etiology. It was initially termed benign intracranial hypertension (BIH); however, its association with visual loss discouraged the term. Idiopathic intracranial hypertension is a syndrome characterized by elevated intracranial pressure with its associated signs and symptoms (headache, pulsatile tinnitus, papilledema) in an alert and oriented individual, in the absence of focal neurological deficits except for lateral rectus (LR) palsy. Idiopathic intracranial hypertension is typically diagnosed by modified Dandy’s criteria.[1] However, the criteria have been further revised by Friedman et al.[2] to incorporate recent insights into the disease.

Idiopathic intracranial hypertension is associated with many endocrine diseases (hypothyroidism, hyperthyroidism, Addison’s disease, or hypoparathyroidism), therapies [levothyroxine (LT4), recombinant growth hormone, leuprolide acetate, levonorgestrel, or anabolic steroids] and withdrawal from chronic corticosteroids.[2] Idiopathic intracranial hypertension following LT4 replacement is extremely rare, with only a few cases being reported in the literature, most being in the pediatric age group.

Several risk factors and mechanisms for the development of IIH following LT4 therapy have been proposed, but the exact cause remains elusive.[3,4] Though Campos et al.[4] have summarized the literature published till 1995 on IIH following LT4 replacement, a systematic evaluation of this entity is lacking. Hence, we report a patient who developed classical IIH following LT4 replacement and performed a systematic review of the literature on IIH following LT4 replacement in hypothyroid patients.


Case report

This study includes a report of a patient with IIH following LT4 replacement for the management of primary hypothyroidism. Written informed consent was obtained from the patient. The case record of the patient was reviewed and relevant information was noted.

Systematic review

The systematic review was performed following the PRISMA guidelines. The Pubmed database was searched using search terms ‘idiopathic intracranial hypertension AND hypothyroidism’, ‘benign intracranial hypertension AND hypothyroidism’, ‘pseudotumor cerebri AND hypothyroidism’, and ‘intracranial hypertension AND hypothyroidism’. The search yielded a total of 44 articles including 6 articles identified through cross-references. No duplicates were found. Of the 44 articles, 22 were excluded by title and abstract screening for various reasons [Figure 1]. Among the remaining 22 records, 2 were excluded as the minimum essential case details could not be retrieved.[5,6] Among the remaining 20 articles, 2 were excluded as IIH had occurred before the initiation of LT4 replacement.[7,8] The remaining 18 articles yielded a total of 21 cases that were included in this systematic review.[3,4,9–24]

Figure 1:
Preferred reporting items for systematic reviews and meta-analyses flow diagram for selecting of articles for systematic review

In older case reports where patients were treated with liotrix (n = 2),[9,12] or liothyronine (n = 1),[11] conversion to equivalent doses of LT4 was done.[25] Hereafter, LT4 refers to LT4 and/or LT4 equivalents. LT4 doses of 10-15, 4-6, 3-5, 2-4, and 1.8 μ were considered as the recommended replacement range for infants, 1-3 years of age, 3-10 years of age, 10-16 years of age and >16 years of age, respectively.[26] The cumulative dose of LT4 was calculated as the total amount of LT4 received from the initiation/latest re-initiation of LT4 till the diagnosis of IIH. The daily dose was calculated by dividing the cumulative dose by the number of days of LT4 replacement. The ratio of initial and daily LT4 doses (μ to the maximum recommended age-specific LT4 replacement dose was calculated.

Statistical analysis

Data were analyzed using the statistical package for social sciences, version 21, Armonk, NY: IBM Corp. Continuous variables were presented as median with inter-Quartile Range (Q1- Q3) and categorical variables were presented as a percentage. The spearman correlation test was to assess correlation among non-parametric variables. A P value of <0.05 was considered statistically significant.


Case report

A 46-year-old woman had been diagnosed with primary hypothyroidism a month ago by a primary care physician during evaluation for dry skin, constipation, lethargy, excessive sleepiness, cold intolerance, and memory disturbances for the past 2 years. She reported no headache, blurring of vision, or diplopia. Her TSH and free T4 were 319 mIU/L, and 0.04 ng/dl, respectively, and she was started on LT4 replacement (100 μg.d).

She presented to us a month later with gradually increasing, continuous, holo cranial headache for 15 days which was more in the supine position and upon waking up from sleep. It was associated with photopsia, nausea, vomiting, blurring of vision, and diplopia on lateral gaze. On examination, she was obese (body mass index: 28.3 kg/m2), and had normal vitals with grade 1, firm, non-tender goiter. She had bilateral lateral rectus (LR) palsies with reduced visual acuity (right: 6/24, left: 6/36). On fundus examination, bilateral papilledema with splinter hemorrhages and absent spontaneous venous pulsations (SVP) was observed [Figure 2a and b]. Other neurological and systemic examination findings were normal. Her serum TSH, T4, T3, and 8:00 am cortisol levels were 21.52 mIU/L, 12.35 μg/dl, 0.85 ng/ml, and 17.19 μg/dl, respectively.

Figure 2:
Fundus examination showing bilateral papilledema with splinter hemorrhages and absent spontaneous venous pulsations at diagnosis of idiopathic intracranial hypertension (a and b); complete resolution of papilledema with normal optic disc and spontaneous venous pulsations three months later (c and d)

MRI brain revealed a partially empty sella [Figure 3a and b]. LT4 replacement was withheld and a guarded lumbar puncture was done. Cerebrospinal fluid (CSF) opening pressure was 32 cm of H2O with otherwise normal CSF analysis. Thirty ml of CSF was drained following which the patient reported immediate improvement in headache, with a resolution of headache and improvement in diplopia and LR palsies by 24 hours and in subjective vision by 48 hours. She was started on acetazolamide 250 mg thrice daily and reinitiated on LT4 25 μg.d for 2 weeks followed by 50 μg for 2 weeks followed by 75 μg for 2 weeks and 88 μg thereafter. Three months later, she had no headache, nausea, vomiting, and visual symptoms. Her extra-ocular movements were normal in all directions and the fundus revealed complete resolution of papilledema with normal optic disc and spontaneous venous pulsations [Figure 2c and d]. Her TSH, T4, and T3 were 5.55 mIU/L, 10.85 μg/dl, and 0.75 ng/ml, respectively. She was continued on 88 μg of LT4.

Figure 3:
T2-weighted sagittal (a) and T1-weighted coronal (b) magnetic resonance imaging of brain revealed a partial empty sella

Systematic review

The median age of the patients was 13 years (n = 21; IQR: 8.87- 26.5 years), with only 6 cases occurring in adults. Male to Female ratio was 1:2 with 7 cases in males and 14 in females. The median duration of hypothyroid symptoms at the diagnosis of hypothyroidism was 4 (n = 10, IQR: 0.44-6.25) years. In 11 patients, including four of the six adult patients, the duration of symptoms was not available. The median time to onset of IIH symptoms and diagnosis of IIH from initiation of LT4 replacement was 1.5 (n = 19, IQR: 0.75-4) months and 2 (n = 20, IQR: 1.17-4) months, respectively [Table 1].

Table 1:
Demographic, hypothyroidism and levothyroxine replacement-related characteristics of idiopathic intracranial hypertension patients following levothyroxine replacement

Eye examination findings were recorded for 19 patients of whom papilledema, absent SVP, and retinal hemorrhages were recorded in 18 (94.7%), 4 (21.05%), and 2 (10.52%) patients, respectively. Lateral rectus palsy was seen in 6 patients (31.5%) and was bilateral in three patients. Enlargement of blind spot was present in three patients whereas a decrease in visual acuity was seen in one patient (5.26%). The median CSF opening pressure was 35 (n = 11, IQR: 27.4-40) cm of H2O [Table 2].

Table 2:
Ophthalmological and imaging characteristics at the time of diagnosis of idiopathic intracranial hypertension

Twelve of 19 (63.1%) patients had imaging features of raised ICT. Imaging findings observed were empty sella (n = 2), enlargement of sella (n = 2), decreased volume of lateral ventricles/ventricular compression (n = 3), enlarged optic nerve (n = 1), dilatation of choroidal sheaths of both optic nerves (n = 1) and other signs of raised ICT such as coronal suture diathesis, spreading of sutures and demineralization of the calvaria, separation of coronal sutures, split sutures.

The median serum TSH and T4 at LT4 initiation were 100 (n = 14, IQR: 72.5-421.6) mIU/L, and 1.13 (n = 12, IQR: 1.0-2.45) μg/dl, respectively whereas those at the diagnosis of IIH were 2.2 (n = 7; IQR: 0.23-3.40) mIU/L and 8.90 μg/dl (n = 8, IQR: 6.43-14.85 μg/dl), respectively. The median initial LT4 doses were 50 (n = 18, IQR: 50-81.25) μg.d, 3.44 (n = 9, IQR: 0.91-5.2) μ, and 0.87 (n = 8, 0.26-1.11) times the maximum recommended dose for age. The median cumulative LT4 dose at the diagnosis of IIH was 5437.5 (n = 18, IQR: 3281.2-12862.5) μg. The median daily LT4 doses were 94 (n = 18, IQR: 59-141.6) μg, 3.91 (n = 8; IQR: 2.60-6.28) μ, and 0.89 (n = 8, IQR: 0.60 – 1.17) times the maximum recommended dose for age.

There was no significant correlation of age, gender, duration of hypothyroid symptoms, thyroid function parameters (TSH and T4) at LT4 initiation and IIH diagnosis, LT4 therapy-related parameters (initial, and daily LT4 doses as per day, per day per kg of body weight and a number of times the maximum recommended dose for age) with CSF opening pressure or lateral rectus palsy (data not shown).

The various approaches for IIH management included watchful observation, reduction in dose of thyroid hormone replacement, CSF drain via lumbar puncture (often repeated), acetazolamide, glucocorticoids, and glycerol [Table 3]. The watchful observation was done in three patients in whom the symptoms resolved spontaneously but slowly over 1-9 months. Reduction/discontinuation of thyroid hormone replacement alone was effective in three patients with resolution of IIH in 2 weeks whereas, in two others, initial management with thyroid hormone replacement reduction resulted only in transient/incomplete resolution. Glucocorticoids (dexamethasone, prednisolone, cortisone acetate, or parental steroids) were used in six patients but the regimens were heterogeneous. Notably, recurrences occurred in a patient who was initially managed with long-duration isolated glucocorticoid therapy (high dose) and another who received high-normal replacement glucocorticoid doses following a CSF drain procedure. However, high-dose oral glucocorticoid use following a CSF drain procedure (n = 1) or adjunctive use of a short course of steroids (oral or parenteral) along with other intracranial pressure-lowering measures (n = 3) was beneficial. The triple regimen including CSF drain, acetazolamide, and thyroid hormone replacement dose reduction resulted in relatively faster and long-term resolution of IHH in all (n = 4) whereas single CSF drain procedure as the initial monotherapy did not provide long-term remission (n = 2). Notably, CSF drain and acetazolamide without thyroid hormone replacement reduction resulted in IIH resolution in one patient. All patients (n = 20) had a resolution of IIH at the last follow-up.

Table 3:
Management and outcome of idiopathic intracranial hypertension following thyroxine replacement


We report an adult woman with typical IIH following LT4 replacement for the management of primary hypothyroidism. This first systematic review on IIH following LT4 replacement identified 21 additional cases. The review summarizes the patient characteristics of IIH following LT4 replacement and analyzes its predictors. Pediatric-age patients, prolonged symptom duration, marked hypothyroidism (TSH of ≥100 mIU/L and low T4), and use of higher initial and cumulative LT4 doses was frequent in these patients which may suggest their association with IIH.

The patient from our center had severe primary hypothyroidism (undetectable T4) of prolonged duration (4 years) and was initiated on full LT4 replacement with rapid improvement in thyroid function tests. As noted in the systematic literature review, prolonged symptom duration, marked hypothyroidism and higher initial replacement with rapid changes in thyroid function often characterized IIH development following LT4 replacement. The median time to develop IIH symptoms was 1 month in the systematic review; however, our patient developed a headache relatively earlier (15 days). Also, our patient had splinter hemorrhages and bilateral lateral rectus palsy which were rarer in other LT4-related IIH patients. An earlier onset and greater severity of IIH in our patient may be due to a stronger association with the aforementioned risk factors. Notably, our patient was also obese, a well-known risk factor for IIH. The prevalence of IIH in the general population is 1-3/100,000/year with a higher prevalence in obese women of reproductive age (21/100,000/year).[27] There are also a few case reports of IIH in untreated hypothyroidism patients.[7,8] So, although LT4 replacement is the most likely cause of IIH in our patient, the contribution of hypothyroidism perse or obesity cannot be excluded. Another interesting finding in our patient is a rapid and complete response including complete reversal of papilledema despite established papilledema. Such a prompt response may be attributed to a short duration of IIH and timely effective therapy. The triple regimen used in our patient (LT4 dose reduction/temporary discontinuation, CSF drain, and acetazolamide) has been shown to provide relatively rapid and long-term remission in the previously reported cases.

In the systematic review, only 21 cases of IIH following LT4 replacement were identified suggesting it is a rare entity. However, underdiagnosed and underreporting of such cases cannot be ruled out. The majority of the patients reported with the condition are children and adolescents which may represent their increased susceptibility or a tendency for rapid normalization of thyroid function by initiating or rapidly titrating to higher LT4 replacement doses in them. Notably, in the last two decades, the proportion of children has reduced which may reflect an increased awareness among the pediatricians/pediatric endocrinologist regarding the condition.

The mechanisms underlying LT4-related IIH are not well-elucidated. Altered CSF dynamics with rapid correction of hypothyroidism, possibly related to maladaptation to rapid changes in TRH and/or vasopressin may lead to IIH. Accentuation of hypocortisolism due to the increased cortisol metabolism with LT4 initiation has also been proposed as an alternative mechanism. Besides, associated obesity, a well-known risk factor for IIH, may also contribute.[4] Although greater information is available on the risk factors (younger age, prolonged and severe hypothyroidism, higher LT4 dose), the absence of these risk factors in some patients warrants a search for other unknown factors.

Papilledema was the most common noninvasive finding observed (94.7%) whereas other eye findings were less frequent. Notably, the imaging evidence of raised ICT was observed in only 63% of patients. MRI and MRV were also often normal. Hence, we suggest that imaging is not sensitive for the diagnosis of LT4-related IIH, although it is essential to exclude organic causes of raised ICT. In contrast, lumbar puncture revealed elevated CSF pressure in most of the patients which also provides an opportunity for drainage of CSF fluid, a therapeutic intervention. IIH patients may be at risk of blindness (incidence: 1-2 per 100 cases per year).[27] Although the therapeutic regimens in the cases were widely heterogeneous, a triple regimen (LT4 dose reduction/temporary discontinuation, CSF drain, and acetazolamide) appears to be the most effective therapy for IIH resolution; hence, can be preferred in patients with severe IIH, especially in those with reduced visual acuity. However, with watchful observation, LT4 dose reduction/temporary discontinuation, and/or oral acetazolamide may be effective in some cases; hence, one of these approaches may be considered in milder IIH cases.


A small number of subjects with heterogeneous data, missing details in several patients, and predominance of pediatric patients, in whom the analysis is weight- and age-dependent, are a few limitations of the systematic review. Nevertheless, this is the first systematic review of this rare entity. The study also includes a detailed description of an adult patient with LT4-related IIH from our center.


We report an adult woman with IIH following LT4 replacement for primary hypothyroidism, an extremely rare entity, especially in adults. Pediatric-age patients, prolonged symptom duration and use of higher initial and cumulative LT4 doses were frequent and may be associated with IIH following LT4 replacement. A triple regimen (LT4 dose reduction/temporary discontinuation, CSF drain, and acetazolamide) may be the most effective therapy for the management of IIH following LT4 replacement. Further prospective studies are warranted to elucidate risk factors and mechanisms underlying LT4-related IIH.

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Conflicts of interest

There are no conflicts of interest.


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                          Hypothyroidism; idiopathic intracranial hypertension; papilledema; pseudotumor cerebri; thyroxine

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