Porphyria-induced posterior reversible encephalopathy syndrome and central nervous system dysfunction

Molecular Genetics and Metabolism xxx (xxxx) xxx–xxx

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Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme

Review article

Porphyria-induced posterior reversible encephalopathy syndrome and central nervous system dysfunction Daniel A. Jaramillo-Callea,b, Juan M. Solanoc, Alejandro A. Rabinsteind, Herbert L. Bonkovskye,

⁎

a

IPS Universitaria, Universidad de Antioquia, Medellin, Colombia Institute of Medical Research, Universidad de Antioquia, School of Medicine, Medellin, Colombia c Department of Neurology, Universidad de Antioquia, School of Medicine, Medellin, Colombia d Department of Neurology, Mayo Clinic, Rochester, MN, United States of America e Section on Gastroenterology & Hepatology, Wake Forest University School of Medicine/NC Baptist Hospital, Winston-Salem, United States of America. b

A R T I C LE I N FO

A B S T R A C T

Keywords: Central nervous system Neuroimaging Neuropsychiatry Physiopathology Porphyria Posterior leukoencephalopathy syndrome

Background and aim: An association between neuropsychiatric manifestations and neuroimaging suggestive of posterior reversible encephalopathy syndrome (PRES) during porphyric attacks has been described in numerous case reports. We aimed to systematically review clinical-radiological features and likely pathogenic mechanisms of PRES in patients with acute hepatic porphyrias (AHP) and porphyric attacks. Methods: PubMed, Scopus, Ovid MEDLINE, and Google Scholar were searched (July 30, 2019). We included articles describing patients with convincing evidence of an AHP, confirmed porphyric attacks, and PRES in neuroimaging. Results: Forty-three out of 269 articles were included, which reported on 46 patients. Thirty-nine (84.8%) patients were women. The median age was 24 ± 13.8 years. 52.2% had unspecified AHP, 41.3% acute intermittent porphyria, 4.3% hereditary coproporphyria, and 2.2% variegate porphyria. 70.2% had systemic arterial hypertension. Seizures, mental changes, arterial hypertension, and hyponatremia occurred more frequently than expected for porphyric attacks (p < .001). Seizures and hyponatremia were also more frequent than expected for PRES. The most common distributions of brain lesions were occipital (81.4%), parietal (65.1%), frontal (60.5%), subcortical (40%), and cortical (32.5%). Cerebral vasoconstriction was demonstrated in 41.7% of the patients who underwent angiography. 19.6% of the patients had ischemic lesions, and 4.3% developed long-term sequelae (cognitive decline and focal neurological deficits). Conclusions: Brain edema, vasoconstriction, and ischemia in the context of PRES likely account for central nervous symptoms in some porphyric attacks.

1. Introduction Posterior reversible encephalopathy syndrome (PRES) is a clinicalradiological condition characterized by neurological symptoms and cerebral vasogenic edema. Clinical manifestations include seizures, headaches, altered mental status, visual disturbances, and other focal neurological deficits. Neuroimaging often shows asymmetric and bilateral vasogenic edema, predominantly affecting parieto-occipital

regions, which is often reversible in follow-up images. PRES was initially observed in association with preeclampsia/eclampsia, renal failure, cytotoxic drugs, autoimmune disorders, and organ transplantation. However, the increasing availability of advanced imaging technologies in emergency rooms is broadening the spectrum of diseases in which PRES is recognized, such as the acute hepatic porphyrias (AHPs) [1,2]. AHPs are rare genetic disorders characterized by partial enzymatic

Abbreviations: ADH, Antidiuretic hormone; AHPs, Acute hepatic porphyrias; AIP, Acute intermittent porphyria; ALA, 5-aminolevulinic acid; ALAS1, 5-aminolevulinic acid synthase 1; BBB, Blood-brain barrier; CNS, Central nervous system; CSF, Cerebrospinal fluid; GABA, γ; ICAM1, Intracellular adhesion molecule-1; IL, Interleukin; IQR, Interquartile range; MAP, mean arterial pressure; NO, Nitric oxide; NOS, Nitric oxide synthase; PEPT2, Peptide transporter 2; PRES, Posterior reversible encephalopathy syndrome; PTX3, Pentraxin-3; ROS, Reactive oxygen species; SIADH, Inappropriate secretion of ADH; TCAC, Tricarboxylic acid cycle; TNF, Tumor necrosis factor; ULN, Upper limit of normal; UPBG, Urinary porphobilinogen; VCAM1, Vascular cell adhesion protein-1; VEGF, Vascular endothelial growth factor ⁎ Corresponding author at: Wake Forest University, School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, United States of America. E-mail addresses: [email protected] (D.A. Jaramillo-Calle), [email protected] (H.L. Bonkovsky). https://doi.org/10.1016/j.ymgme.2019.10.011 Received 12 August 2019; Received in revised form 29 October 2019; Accepted 30 October 2019 1096-7192/ © 2019 Published by Elsevier Inc.

Please cite this article as: Daniel A. Jaramillo-Calle, et al., Molecular Genetics and Metabolism, https://doi.org/10.1016/j.ymgme.2019.10.011

Molecular Genetics and Metabolism xxx (xxxx) xxx–xxx

D.A. Jaramillo-Calle, et al.

2.3. Study selection and data collection

deficiencies in the heme biosynthetic pathway. The most common forms are autosomal dominant inherited disorders, named acute intermittent porphyria (AIP, OMIM:176000), hereditary coproporphyria (OMIM:121300), and variegate porphyria (OMIM:176200). A fourth and very rare recessive form is caused by a severe deficiency of 5aminolevulinic acid dehydratase (OMIM:125270). The clinical presentation consists of life-threatening attacks of neurovisceral symptoms due to autonomic, peripheral and central neuropathy. Signs and symptoms are nonspecific, typically comprising abdominal pain, tachycardia, systemic arterial hypertension, bladder dysfunction, vomiting, pain, and muscle weakness. Central nervous system (CNS) dysfunction and neuropsychiatric manifestations similar to those of PRES may also occur in a minority of cases. Attacks are triggered by factors (e.g., drugs, fasting, stress, alcohol, hormones) that induce hepatic 5-aminolevulinic acid synthase 1 (ALAS1, E.C. 2.3.1.37) and cause excessive production of the porphyrin precursors, 5-aminolevulinic acid (ALA) and porphobilinogen. Symptoms rarely occur before puberty and are more common in women, probably related to the inducing effect of sex hormones (predominantly progesterone) on ALAS1. Diagnosis relies on the demonstration of significantly elevated urinary ALA and/or porphobilinogen (UPBG). Intravenous hemin is considered the most effective treatment available for attacks, but carbohydrate loading may also be useful in mild cases [3]. The pathogenesis of attacks is not entirely understood [4]. The most widely accepted hypothesis suggests that ALA produced excessively in the liver is the main pathogenic factor [5]. ALA can inhibit or activate γ-aminobutyric acid receptors and is also pro-oxidative so that it may lead to neuro and cytotoxicity [6,7]. The fact that liver transplantation stops recurrences of attacks and normalizes the urinary excretion of porphyrin precursors supports that the liver is the primary pathogenic site. However, an important unresolved issue regarding this hypothesis is to what extent excessive ALA synthesized in the liver is involved in the pathogenesis of CNS dysfunction given that the blood-brain barrier (BBB) is almost impermeable to porphyrin precursors, and there is a clearance mechanism at the choroid plexuses to maintain the concentration of ALA low in the brain [8]. Recently, many patients with neuropsychiatric manifestations and neuroimaging suggestive of PRES during porphyric attacks have been identified. It is unknown whether these two phenomena always occur together, but cerebral edema and vasoconstriction related to PRES are plausible explanations for CNS dysfunction during porphyric attacks. Nevertheless, this relationship has not been systematically studied. Here, we present a systematic review of published case reports and series to characterize the clinical-radiological features of PRES during porphyric attacks and discuss possible pathogenic mechanisms to explain this relationship.

Two reviewers (DAJC and JMS) independently screened abstracts and collected the data. Articles in languages other than Spanish and English were translated. Extracted data included age, sex, medical history, clinical manifestations, laboratory tests, medications, imaging studies, and outcomes. Unreported data were considered absent. Disagreements were resolved by discussion to a consensus between reviewers. Relevant missing data were requested from authors. 2.4. Methodological quality assessment We used the tool to assess the methodological quality of case reports by Murad et al. [9], which was adapted for this review. The quality was judged according to the number of criteria fulfilled as high (5 criteria), moderate (4 criteria), and low (≤3 criteria). 2.5. Diagnosis of porphyric attacks To establish that a group of nonspecific clinical manifestations is caused by a dominant AHP, significantly elevated UPBG must be demonstrated [10]. In this review, confirmed porphyric attacks were defined as concentrations of UPBG ≥ 4-fold the upper limit of normal (ULN) or positive qualitative tests. Quantitative UPBG tests are best normalized to urine creatinine concentrations, which adjust to the marked variability related to the concentration or dilution of urine. Quantitative UPBG tests reported as elevated without reference ranges were considered positive. 2.6. Study parameters Severe porphyric attacks were defined by the presence of hyponatremia (serum Na < 130 mEq/L), seizures, or paresis. Otherwise, they were considered mild. Porphyria types were reassessed based on DNA analysis, erythrocyte hydroxymethylbilane synthase activity, and porphyrin analysis [11]. Seizures were classified as generalized, focal, or unknown [12]. Systemic arterial hypertension was defined as blood pressure ≥ 95th percentile (< 13 years), ≥130/80 (13–16 years), and ≥ 140/90 (≥17 years) [13,14]. Mean arterial pressure (MAP) was calculated as 1/3 systolic blood pressure + 2/3 diastolic blood pressure. It was graded as normal (≤105 mmHg), slightly elevated (106–115), and significant hypertension (≥116) [15]. Hyponatremia was categorized as mild (Na ≤ 135), moderate (Na = 125–130), and profound/severe (Na < 125) [16]. Brain lesions distribution was categorized as lobar (frontal, parietal, occipital, temporal), cerebellum, brain stem, basal ganglia, cortical, and subcortical. Topographic patterns were classified as dominant parieto-occipital, holo-hemispheric watershed, and superior frontal sulcus [15].

2. Methods

2.7. Data analyses

2.1. Eligibility criteria

Continuous variables were summarized as medians/interquartile ranges (IQR) and categorical variables as counts/percentages. One sample proportion Z-test was used to compare relative frequencies of seizures, mental changes, hypertension, and hyponatremia in this review against theoretical relative frequencies of the same manifestation during porphyric attacks derived from published series [17–19]. As ~30% of asymptomatic AHPs mutation carriers have a high UPBG (up to 15-fold ULN), we compared demographic and clinical features of patients with UPBG≥15-fold and patients with UPBG < 15-fold or positive qualitative tests to evaluate the impact of a possible misclassification. The median age was compared using the Wilcoxon ranksum test and categorical variables using the chi-squared test or Fisher's exact test. Two-sided p-values < .05 were considered statistically significant. Analyses were performed in Stata Statistical Software, V.14 (College Station, TX: StataCorp LP.).

We included any study describing patients with AHPs who developed PRES during porphyric attacks and that provided data at the single-subject level. To be included, patients had to have 1) convincing clinical evidence of an AHP, 2) confirmed porphyric attacks, and 3) a description of PRES in head MRI or CT scans. Articles were excluded if alternative etiologies of PRES were identified [1] or double report a patient. 2.2. Information sources and search PubMed, Scopus, Ovid MEDLINE, and Google Scholar were searched through July 30, 2019. No restrictions were applied. Reference lists of included studies were reviewed manually (Search strategy in supplements). 2

USA China

Colombia

India

Canada

F/20 F/18

F/18

F/22

F/21

3

C

B

USA Taiwan China USA SK

F/57 F/39 F/9 F/20 F/24

Japon

F/20

AHP

AHP

USA

F/33

AHP AHP

AIP AHP

Germany Turkey

F/20 F/25

AIP AHP AHP

Belgium France

Switzerland Switzerland Pakistan

F/35 F/32 M/20

AIP AIP

AHP

AHP

AHP

AHP

AIP AHP

VP AIP AIP AIP AIP

AIP AIP AIP

HCP AIP AIP AIP

Type

F/43 F/39

USA Japon

F/22 F/29

Taiwan

China Japon USA

F/28 F/38 F/18

M/60

NZ Spain Russia India

F/21 F/23 F/36 F/24

A

Country

Sex/Age

Set

(11) (17) (37) (21) (39)

High (98)

High

High High

High High

High (168) High (87) High (11)

High (12) High (41)

High (70)

High (184)

High

High (4)

High (201) High

High High High High High

High High (52) High (626)

High (15) High (86) High High (34)

UPBG (n-fold ULN)

(132) (137) (120)

(133)

176/93 (121)

NR

200/NR Normal

170/100 (123) 180/120 (140)

NR 170/100 (123) 140/100 (113)

220/NR 135/75 (95)

164/98 (120)

NR

190/110 (137)

150/71 (97)

148/118 (128) 136/101 (113)

193/103 NR 175/110 170/120 160/100

NR 183/114 (137) 160/115 (130)

171 / 125* NR 180/100 (127) NR

BP (MAP)

123

121

132 125

NR

NR NR NR

NR 94

NR

NR

NR

137

NR 104

120 NR NR 128 NR

120 NR NR

125 114 137 129

Na

delirium unconscious paresis, mental changes lethargy

Seizures, paresis, emotional lability

Confusion, blindness, vertigo Paresis, blurred vision, headache, mental changes Seizures, paresis, confusion, apraxia

Seizures, paresis, visual disturbances Seizures, paresis, blindness, unconscious

Seizures, paresis, blindness Seizures, paresis, blindness Seizures, impaired consciousness

Seizures, paresis, psychosis, impaired consciousness, disorientation, confusion Seizures, diplopia, headache Seizures, paresis, unconscious

Seizures

Seizures, paresis, disorientation, somnolence, blindness Seizures, disorientation, blindness

Seizures, lethargy Seizures, hallucinations

Seizures, paresis, dysarthria, unconscious Seizures, impaired consciousness Seizures, confusion, hallucinations, somnolence, disorientation, headache Seizures, paresis, confusion Paresis, headache Seizures, confusion, visual disturbances Seizures, paresis, lethargy, hallucinations Seizures, paresis, visual disturbances

Seizures, Seizures, Seizures, Seizures,

Neurological manifestations

(continued on next page)

[57]

[36]

[57] [35]

[55] [56]

[27] (#1) [27] (#2) [53]

[25] [26]

[52]

[51]

[50]

[46]

[33] [34] (#2)

[22] [23] [24] [28] [31]

MRI = ↑ T2 cortical and subcortical. ↑DWI / ↑ ADC. (RT, LT, RP, LP, RO, LO). MRI = ↑ FLAIR subcortical (RF, LF, RP, LP, RO, LO). Reversible (1 y) MRI = ↑ T2 (RP, LP, RO, LO). Reversible (5 d) MRI = ↑ T2 (RF, LF, RP, LP). Reversible (10 d) MRI = ↑ T2/FLAIR cortical and subcortical. Non-enhancing. ↓ DWI / ↑ ADC (RF, RO, LO, pons, midbrain, thalamus, basal ganglia, left corona radiata). Reversible (2 w) MRI = ↑ T2/FLAIR (RF, LF, LT, RT, RP, LP, RO, LO). Reversible (1 m) MRI = ↑ T2/FLAIR Cortical and Subcortical, ↓ DWI / ↑ ADC (RF, LF, RP, LP, RO, LO) Reversible (2 w). MRA = Normal MRI = ↑ FLAIR Cortical/Subcortical. Enhancing. No restricted diffusion. (LF, RF, LP, RP, LO, RO). Reversible (19 d) MRI = ↑ Cortical and Subcortical (RF, LF, LT, RT, RP, LP) No restricted diffusion. Reversible (14 d) MRI = ↑ FLAIR cortical and subcortical (RF, LF, RP, LP, RO, LO). Reversible (3 w) MRI = ↑ T2/FLAIR cortical and subcortical. Non-enhancing. (RF, LF, RP, LP, RO, LO). Reversible (6 w) MRI = ↑ T2. Non-enhancing. (RO, LO). Partially reversible (5 d). CTA = Normal MRI = ↑ T2. Enhancing. (Caudate nucleus, putamen, pons, and thalamus). Cortical necrosis. Partially reversible (10 m) MRI = ↑ T2 (RO, LO, calcarine). Partially reversible (6 m) – Ischemic lesions MRI = ↑ T2 Subcortical. Enhancing. (RF, RO, LO). Not reversible (4 w) – Ischemic lesions MRI = ↑ T2/FLAIR. Non-enhancing. Restricted diffusion. (RO, LO, parasagittal). Partially reversible (1 w) – Ischemic lesions. MRA = Normal MRI = ↑ T2 (LF, RO, LO). Not reversible (10 d). MRA/CA = Normal MRI = ↑ T2/FLAIR cortical and subcortical ↑DWI / ↓ ADC (RF, LF, RP, LP, RO, LO, LF, RCb, LCb, corpus callosum). Not reversible (6 m). Ischemic lesions MRI = ↑ T2 (RO, LO). Not reversible (36 m) – Ischemic lesions. MRA/CA = Vasoconstriction MRI = ↑ T2 (RP, LP, RO, LO, Cb). ↓ ADC. MRA/CA = Vasoconstriction / thrombosis. CT = Subarachnoid hemorrhage. Partially reversible (6 d) MRI = ↑ T2 cortical. Non-enhancing. (RP, LP). Partially reversible/Ischemic lesions (4 d). MRA/CA = Vasoconstriction MRI = ↑ FLAIR. ↑ DWI / ↑ADC (RP, LP, RO, LO, RF LF, RCb, LCb). Partially reversible (51 d) – Ischemic lesions. MRA = Vasoconstriction

MRI = ↑ FLAIR Cortical and Subcortical. Non-enhancing. (RP, LP, RO, LO). Reversible (6 m) MRI = ↑ FLAIR Subcortical ↑DWI (RO, LO) Reversible (21 d). MRA = Normal MRI = ↑ T2 subcortical. Enhancing. (RF, LF, RT, LT). Reversible (5 w). CA = Vasoconstriction

[32] [54] [58] (#1) [58] (#14) [60] [61] [62]

Ref.

MRI = Edema. Non-enhancing (RP, LP, RO, LO). Reversible (6 w) MRI = ↑ T2 Cortical and Subcortical. Non-enhancing. ↑ ADC (LF, RF). Reversible (2 m) CT = Hypodense lesions (LF, RF, LT, RT). Reversible (1.5 m) MRI = ↑ T2. ↑ DWI / ↓ ADC (RF, LF, RT, LT, RP, LP, RO, LO). Reversible (1.5 m). MRA = Normal

Neuroimaging findings

Table 1 A detailed summary of the included articles. Demographic, clinical, biochemical, and neuroimaging features of patients with PRES during porphyric attacks (n = 46).

D.A. Jaramillo-Calle, et al.

Molecular Genetics and Metabolism xxx (xxxx) xxx–xxx

Spain Spain Taiwan India China India Nepal UK India

France India Colombia SK

SA India

India

F/29 F/20 F/35 M/17 M/27 F/26 F/16 F/26 F/5

F/26 M/17 F/24 F/75

F/12 M/12

M/19

AHP

AHP AHP

AHP AHP AHP AHP

AIP HCP AIP AIP AHP AHP AHP AHP AHP

AIP

Type

(175)

(907)

(39.3) (> 10)

High

High (9) High

High High (23) High High

High High High High High High High High High High High

UPBG (n-fold ULN)

140/100 (113)

166/115 (132) 170/110 (130)

NR 140/110 (120) NR 130/80 (97)

170/80 (110) 177/103 (128) Hypertension 166/111 (129) NR 170/110 (130) 159/101 (120) 160/100 (120) NR NR 100/70 (80)

BP (MAP)

144

131 126

120 120 NR 118

NR NR 128 126 127 128 130 130 126 138 113

Na

Seizures, obtunded, paresis, blindness Impaired consciousness, hallucinations, confusion, disorientation, blindness Seizures, paresis, unconscious, blindness

Seizures, anxiety, blurred vision, headache Seizures, paresis, impaired consciousness Paresis Seizures, paresis, somnolence, mental changes

Seizures, hallucinations, unconscious Seizures, blindness Confusion, blindness Paresis, blurred vision, headache Seizures, paresis Seizures, unconscious Seizures, paresis Seizures, hallucinations, mental changes Seizures, unconscious Seizures, nystagmus Seizures, paresis, somnolence

Neurological manifestations

[20] [21] [59] [29] [30] [34] (#1) [37] [38] [39] [40]

[47] [48] [49]

MRI = ↑ FLAIR cortical and subcortical. ↑ DWI / ↑ADC. (RF, LF, RO, LO) MRI = ↑ FLAIR cortical and subcortical. ↑ DWI (RF, LF, RP, LP, RT, LT, RO, LO, LF, RCb, LCb) MRI = PRES Subcortical (RO, LO) MRI = ↑ T2/FLAIR. ↓ DWI. (RF, RP, LP, RO, LO) MRI = ↑ (RF, LF, RP, LP, RO, LO) MRI = ↑ T2/FLAIR. Enhancing. ↓DWI / ↑ADC (RF, LF, RP, LP, RO, LO) MRI = ↑ T2/FLAIR (RP, LP, RO, LO, LF, RCb, LCb) MRI = PRES MRI = ↑ T2. Non-enhancing. (Diffuse bilateral) MRI = ↑ T2 (RF, RO, LO, parafalcine) CT = Hypodensity (RF, LF, RP, LP, RO, LO) ↑ T2/FLAIR. ↑DWI / ↑ADC. (LF, RP, LP). CTA = Normal MRI = ↑ T2/FLAIR. Isointense DWI / ↑ADC (RP, LP, RO, LO) MRI = PRES MRI = “lesions in bilateral post central gyrus, medial thalami, periventricular, periaqueductal and hypothalamus” ↑ T2/FLAIR cortical and subcortical (RP, LP, RO, LO) CT = Hypodense lesions (RO, LO) MRI = ↑ T2 (RO, LO)

[41] [42] [44] [45]

Ref.

Neuroimaging findings

Set A, Reversible lesions; Set B, Non-reversible lesions; Set C, Non-reversible lesions + cerebral vasoconstriction; Set D, Unreported follow-up neuroimaging. ADC, Apparent diffusion coefficient; AHP, Acute hepatic porphyria (unspecified); AIP, Acute intermittent porphyria; CA, Catheter angiography; CT, Computerized tomography; CTA, Computerized tomography angiography; DWI, Diffusion-weighted imaging; F, Female; FLAIR, Fluid attenuation inversion recovery; GM, Grey matter; HCP, Hereditary coproporphyria; LCb, Left cerebellum; LF, Left frontal lobe; LO, Left occipital lobe; LP, Left parietal lobe; LT, Left temporal lobe; M, Male; MRA, Magnetic resonance angiography; MRI, Magnetic resonance imaging; NR, Not reported; NZ, New Zealand; PRES, Posterior reversible encephalopathy syndrome; RCb, Right cerebellum; Ref, Reference; RF, Right frontal lobe; RO, Right occipital lobe; RP, Right parietal lobe; RT, Right temporal lobe; SA, South Afrika; SK, South Korea; UK, United Kingdom; ULN, Upper limit of normal; UPBG, Urinary porphobilinogen; USA, United States of America; VP, Variegate porphyria. *Maximum systolic and diastolic blood pressure separately.

France

F/62

D

Country

Sex/Age

Set

Table 1 (continued)

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D.A. Jaramillo-Calle, et al.

and alcohol consumption (4.8%, 1/21).

Table 2 Demographic and clinical features of patients with PRES during 47 attacks.

n (%) Attacks, n (%) Demographics Female, n (%) Age, years, median ± IQR Severe attacks CNS manifestations, n (%) Seizures Mental changes Paresis Visual disturbances Headaches Other manifestations, n (%) Abdominal pain Hypertension Tachycardia Vomiting Dark urine Constipation Hyponatremia Treatment, n (%) Hemin Mortality d, n (%)

All patients

UPBG ≥15-fold

UPBG < 15-fold

46 (100) 47 (100)

19 (41.3) 19 (40.4)

27 (58.7) 28 (59.6)

39 (84.8) 24 ± 13.8 46 (97.9)

23 (85.2) 23 ± 15 19 (100)

16 (84.2) 25 ± 14 26 (96.3)

1b 0.92 1b

40 (85.1) 34 (72.3) 25 (53.2) 18 (38.3) 6 (12.8)

17 (89.5) 13 (68.4) 10 (52.6) 5 (26.3) 3 (15.8)

23 (82.1) 21 (75) 15 (53.6) 13 (46.4) 3 (10.7)

0.68 0.62 0.95 0.16 0.67

b

39 33 26 15 13 13 26

(83) (70.2) (55.3) (31.9) (27.7) (27.7) (55.3)

14 (73.7) 13 (68.4) 12 (63.2) 7 (36.8) 4 (21.1) 5 (26.3) 8 (42.1)

25 (89.3) 20 (71.4) 14 (50) 8 (28.6) 9 (32.1) 8 (28.6) 18 (64.3)

0.24 0.82 0.37 0.55 0.40 0.86 0.13

b

28 (59.6) 4 (8.5)

12 (63.2) 1 (5.3)

16 (57.1) 3 (12.0)

0.68 0.62

3.4. Clinical and biochemical features

P-value a

Seizures occurred in 85.1% (40/47) of attacks [generalized: 62.5% (25/40), focal: 17.5% (7/40), unknown: 20% (8/40)]. 70.2% (33/47) had hypertension. Mean arterial blood pressure could be estimated for 30 attacks (median MAP: 123.3, IQR: 17.1 mmHg, range: 80–140), of which 13.3% (4/30) was normal, 13.3% (4/30) slightly elevated, and 73.3% (22/30) significant hypertension. Chronic hypertension was described only in two patients [20,22]. 55.3% (26/47) had hyponatremia. Serum sodium values were available for 25 patients (median Na: 125, IQR: 8 mEq/L, range: 94–132), of which 8% (2/25) had mild hyponatremia, 48% (12/25) moderate, and 44% (11/25) profound/ severe. Acute kidney injury was described in two patients [31,41]. 19.1% (9/47) required mechanical ventilation. CSF analysis was performed in 6 patients; normal results were found in 5 and high glucose levels (98 mg/dL) in 1. One sample proportion Z-test indicated that relative frequencies of seizures, mental changes, hypertension, and hyponatremia in this review were higher than in series of patients with porphyric attacks (Fig. 1).

c

b

3.5. Neuroimaging findings and prognosis

b

Table 4 summarizes neuroimaging findings. Forty-four patients had head MRI and two head CT. Diffusion-weighted images were reported in 13 patients, 10 had non-restricted diffusion, and three restricted diffusion. Follow-up neuroimaging was obtained in 28 patients (median time to follow-up images = 30 days, range: 4–1080 days). Ischemic lesions were detected in 19.6% (9/46) of the patients and were the most common reason for no reversibility in follow-up images [81.8% (9/ 11)]. Two patients had long-term neurological sequelae. The mortality rate was 9.1% (4/44).

IQR, Interquartile range; MAP, Mean arterial pressure; PRES, Posterior reversible encephalopathy syndrome; ULN, Upper limit of normal; UPBG, Urinary porphobilinogen. a Between 4- to 15-fold or positive qualitative test. b p-values for Fisher's Exact tests (Expected counts < 5). c p-values for Wilcoxon rank-sum tests. d Data available for 45 cases. p-values without superscript correspond to Pearson's chi-squared tests.

3. Results 3.1. Study selection and characteristics

4. Discussion Searches provided 269 citations. Sixty-two articles were selected for full-text review, of which 19 articles were excluded (References of excluded articles and PRISMA flow chart in supplements). Reasons for exclusion included unmeasured or low UPBG (n = 17), alternative etiology of PRES (n = 3), and case duplication (n = 1). Forty-three articles were included [39 case reports and 4 case series] [20–62], which reported 46 patients. Patients were from 20 countries in Africa, Asia, Europe, Latin America, North America, and Oceania. A detailed summary of included patients is presented in Table 1. Methodological quality assessment in supplements.

4.1. Pathogenesis of PRES during porphyric attacks

Table 2 summarizes demographic and clinical features. 84.8% (39/ 46) of the patients were women and 15.2% (7/46) men (Ratio of ~5:1), with a median age of 24 and IQR = 13.8 years (Range: 5–75 years).

The pathogenesis of PRES is not entirely understood. Endothelial dysfunction leading to BBB compromise and capillary leakage is considered the central pathogenic process. Given the heterogeneous nature of PRES, various mechanisms may lead to endothelial dysfunction in different clinical scenarios. For example, failed cerebral autoregulation could be caused by severe hypertension, immunological activation, and direct endothelial toxicity [63]. These alterations may occur during porphyric attacks and increase the vulnerability of some patients to develop PRES and CNS dysfunction (Fig. 2) [4,64,65]. Dysfunction of hemoproteins due to heme deficiency, increased oxidative stress, mitochondrial bioenergetic failure, and hyponatremia are mechanisms that may contribute to the development of PRES during porphyric attacks.

3.3. Porphyria diagnosis and precipitating factors

4.2. Hypertension and failed cerebral autoregulation

Porphyria type was confirmed by DNA analysis in 23.9% (11/46) (Table 3), reduced erythrocyte hydroxymethylbilane synthase activity in 17.4% (8/46), and porphyrin analysis in 6.5% (3/46). 52.2% (24/46) of patients had unspecified AHP, 41.3% (19/46) AIP, 4.3% (2/46) hereditary coproporphyria, and 2.2% (1/46) variegate porphyria. Forty-seven porphyric attacks were described, 40.4% (19/47) were confirmed by UPBG ≥ 15-fold and 59.6% (28/47) by UPBG < 15-fold (n = 7) or positive qualitative tests (n = 21). Precipitating factors were identified for 44.7% (21/47) of porphyric attacks, a single precipitant in 71.4% (15/21), and multiple in 28.6% (6/21). They included infections (47.6%, 10/21), caloric deprivation (33.3%, 7/21), medications (14.3%, 3/21), surgery (14.3%, 3/21), acute illness (9.5%, 2/21),

Systemic arterial hypertension occurs in 30–55% of porphyric attacks. It may be the result of sympathetic overactivity, autonomic neuropathy, or higher response to adrenergic agonists in the mesenteric circulation during attacks [10,66,67]. A leading theory of the pathophysiology of PRES indicates that abrupt and severe elevations of blood pressure above the upper limit of cerebral autoregulation (MAP~150 mmHg) lead to vasodilation, hyperperfusion, and compromise of the BBB, resulting in interstitial extravasation of plasma and cerebral vasogenic edema [1]. Therefore, acute systemic arterial and intracranial hypertension and sudden changes in blood pressure might be involved in the pathogenesis of PRES during porphyric attacks. However, only 45.6% of the patients included in this review had

3.2. Demographic characteristics

5

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Table 3 Genetic mutations reported in patients with PRES during porphyric attacks (n = 11). Type

Gene

Nucleotide change

Amino acid change

Ref

Missense

CPOX HMBS HMBS HMBS HMBS CPOX HMBS HMBS HMBS PPOX HMBS

c.863 T > G c.517C > T c.83G > T c.77G > A c.849G > A c.289C > T c.652-2del c.875_876delAA c.651 + 2delT IVS11 + G → C c.88–16.-4delAAGTCTCTACCCGinsCA

p.Leu288Trp p.Arg173Trp p.Ser28Ile p.Arg26His p.Trp283* p.Gln97Xaa p.Gly218_Leu257del p.Gln292Argfs*14

[32] [43] [54] [58] (#1) [20] [59] [58] (#14) [60] [61] [22] [23]

Nonsense Deletion

Splice site Complex Rearrangement

CPOX, Coproporphyrinogen oxidase; HMBS, Hydroxymethylbilane synthase; PPOX, Protoporphyrinogen oxidase; PRES, Posterior reversible encephalopathy syndrome; Ref, Reference.

Fig. 1. Seizures, mental changes, hypertension, and hyponatremia during porphyric attacks with PRES compared to porphyric attacks in general [17–19]. *p < .001 for one sample proportion Z-test.

ALA movement through BBB is mainly by passive diffusion with a meager influx rate (~0.2 mg per min), which leads to cerebral levels that are ~1% of plasma levels [73]. Studies in AIP mice and patients with porphyric attacks have shown no accumulation of ALA in the brain and cerebrospinal fluid (CSF) despite significant elevations in plasma [71,72,74–76]. Unlike BBB, there is a saturable transport mechanism for ALA in the blood-CSF barrier via peptide transporter 2 (PEPT2). PEPT2 catalyzes ALA transport by coupling its translocation with a transmembrane electrochemical proton gradient generating the driving force. It keeps ALA CSF levels low compared to plasma and exerts a neuroprotective effect against ALA toxicity [73]. In this regard, a functional polymorphism in PEPT2, which affects the tightness of binding of ALA to the transporter, and which has been shown to influence the likelihood of progressive renal disease in AHP, may be relevant. PEPT2 has two major variants designated PEPT2*1 (higher ALA affinity) and PEPT2*2 (lower ALA affinity) [77]. PEPT2*2 carriers may have lower ALA brain efflux, which results in more significant neurotoxicity. For instance, children with the PEPT2*2 variant and lead poisoning have poorer motor dexterity and working memory, presumably because of reduced ALA brain clearance [78]. In a recent study of 122 patients with genetically confirmed AIP and PEPT2 genotyping, 26% of the patients were PEPT2*2 carriers [79]. cis-Acting polymorphisms can impair PEPT2 expression [77]. After exogenous administration of ALA, PEPT2-deficient mice exhibit ~30-fold higher ALA

significant hypertension, and MAP was within the limits of cerebral autoregulation in all of them. Besides, there were two patients with chronic hypertension, which causes adaptive vascular changes that adjust the range of cerebral autoregulation to higher blood pressures. These findings suggest that there likely are other additional contributing factors involved in the pathogenesis of PRES during porphyric attacks [68]. Nevertheless, it is important to consider that blood pressure may not have been measured when it was at maximal values. Also, pronounced and rapid fluctuations of blood pressure over baseline values may be more important than the absolute increment [69]. Finally, in some susceptible patients, acute hypertension can lead to endothelial dysfunction even when the increment in blood pressure does not exceed the limits of cerebral autoregulation. An alternative theory proposes that PRES is a consequence of brain hypoperfusion and ischemia caused by endothelial dysfunction from diverse systemic toxic insults (e.g., cytotoxins, immunogens, and neuropeptides) [68]. These toxic insults may occur during porphyric attacks, which may account for PRES in normotensive patients and hypertensive patients with blood pressure within the limits of cerebral autoregulation.

4.3. Central nervous system and porphyrin precursors toxicity The BBB is virtually impermeable to porphyrin precursors [70–73]. 6

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CSF levels, lower survivability, and a worse neuromuscular function compared to wild-type mice [73]. Therefore, patients carrying these polymorphisms may have a greater susceptibility to develop PRES and CNS dysfunction during porphyric attacks. To date, however, studies of PEPT2 variants have not been reported in patients with AHP and PRES. Porphyrin precursors are probably not involved in the initial brain injury during porphyric attacks given that BBB impermeability and PEPT2 limits brain exposure to them. One patient with variegate porphyria developed encephalopathy and seizures during an attack despite low concentrations of ALA and PBG in the CSF [76], which suggests that either porphyrin precursors are very potent neurotoxins or that other factors were involved. However, after BBB compromise or PEPT2 dysfunction, porphyrin precursors might secondarily accumulate in the brain and cause direct injury. Studies in mice have shown that direct administration of ALA and PBG into the lateral ventricle of the brain (i.e., avoiding the BBB) causes seizures in a dose-dependent manner [7]. ALA molecular structure resembles that of the neurotransmitters gamma-aminobutyric acid and L-glutamate, which allow it to interact with their receptors [6]. These alterations might explain the higher incidence of seizures in this review compared to previous reports of PRES (60–75%) or porphyric attacks (20–30%) [1,19,80]. However, unprovoked seizures outside attacks are rare in patients with AHPs, as well as in those who have recovered from PRES [81]. The defective function of the BBB may occur as porphyric attacks progress due to ALA vascular toxicity, endothelial dysfunction, systemic inflammation, and mitochondrial bioenergetic failure. Likewise, the

Table 4 Neuroimaging findings in patients with PRES during porphyric attacks (n = 43). N (%) Brain lesion distribution Occipital lobes Parietal lobes Frontal lobes Temporal lobes Cerebellum Basal ganglia Brainstem Subcortical Cortical Topographic patterns Dominant parieto-occipital Holohemispheric watershed Superior frontal sulcus Contrast medium Enhancement Non-enhancement Follow-up images Reversible findings Partially reversible Non-reversible Angiographic studies Normal caliber arteries Signs of vasoconstriction

43 (91.5) 35 (81.4) 28 (65.1) 26 (60.5) 7 (16.3) 5 (11.6) 2 (4.6) 2 (4.6) 19 (44.2) 16 (37.2) 40 (85.1) 22 (55) 14 (35) 4 (10) 13 (27.6) 5 (38.5) 8 (61.5) 28 (59.6) 17 (60.7) 7 (25) 4 (14.3) 12 (25.5) 7 (58.3) 5 (41.7)

PRES, Posterior reversible encephalopathy syndrome.

Fig. 2. Proposed pathogenic model for brain edema and CNS dysfunction during porphyric attacks. Initiating event: Exposure to factors that increase the demand or degradation of heme upregulates ALAS1, leading to the excessive synthesis of toxic porphyrin precursors (ALA and PBG). Inflammation: ALA pro-oxidative effect might cause organ damage and the release of inflammatory mediators. Cytokines induce the expression of adhesion molecules (ICAM-1, VCAM-1, E-selectin, Pselectin), which interact with leukocytes and potentiate ROS production. ROS, ALA, and PTX3 might cause direct endothelial cell injuries, increasing the expression of VEGF and vascular permeability. Mitochondrial bioenergetic failure: Increased heme utilization might cause a relative deficiency that reduces activities of respiratory chain complexes. Besides, upregulated ALAS1 might increase the demand for succinyl-CoA for ALA synthesis, causing cataplerosis of the TCAC with a low supply of reduced cofactors. These alterations might cause mitochondrial bioenergetic failure and enhance ROS production. A low ATP supply impairs energy-dependent processes, such as PEPT2 and NA+/K+ ATPase function. ADH excess: ALA neurotoxicity and the effect of IL-6 in the hypothalamus might lead to an increment in ADH secretion. ADH inhibits NA+/K+ ATPase and induces NKCC2 and AQP4 in astrocytes, leading to increase ion/water influx and swelling. ADH excess may also lead to hyponatremia. NO deficiency: PTX3, heme deficiency and ROS might impair NOS function, thus decreasing NO synthesis and causing endothelial dysfunction. PEPT2 dysfunction: The PEPT2*2 variant has a lower affinity for ALA than PEPT2*1, which might cause a diminished ALA efflux in choroid plexus and a more significant ALA neurotoxicity in the brain. Hyponatremia, low CSF pH, and lack of ATP might also reduce PEPT2 function. These pathological processes do not necessarily occur in the order described, nor are all present in each patient. Besides, their individual impact is probably small and differs between them. The vulnerability to BBB compromise probably increases progressively as more abnormalities occur and act synergistically. The concurrence of multiple factors related to the porphyria, the patient, and certain precipitants is probably necessary to cause PRES and CNS dysfunction. ADH, Antidiuretic hormone; ALA, 5-Aminolevulinic acid; ALAS1, 5-Aminolevulinic acid synthase-1; AQP4, Aquaporin-4; BBB, Blood-brain barrier; ICAM1, Intracellular adhesion molecule-1; IL, Interleukin; NKCC1, Na+ K+ 2Cl− Cotransporter 1; NO, Nitric oxide; NOS, Nitric oxide synthase; PBG, Porphobilinogen; PEPT2, Peptide transporter-2; PTX3, Pentraxin-3; ROS, Reactive oxygen species; SON, Supraoptic nucleus; SPV, Supraventricular nucleus; TCA, Tricarboxylic acid cycle; TNF, Tumor necrosis factor; VCAM1, Vascular cell adhesion protein-1; VEGF, Vascular endothelial growth factor. 7

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mitochondrial DNA [86]. Bioenergetic failure might increase the susceptibility to develop brain edema and ALA neurotoxicity by impairing energy-dependent processes, such as PEPT2 function and sodium transport in glial cells. Mitochondrial dysfunction also modifies Ca++ homeostasis, intensifies ROS production, and induces apoptosis [99], factors that can lead to endothelial dysfunction and PRES.

PEPT2 transport rate may be impaired by conditions that change CSF pH and electrochemical gradient generated by the Na+/H+ exchanger (e.g., respiratory acidosis or hyponatremia) [82,83]. Remarkably, 60.8% of the patients in this review either required mechanical ventilation or had hyponatremia. 4.4. Immunological activation and endothelial dysfunction

4.6. Reversible cerebral vasoconstriction PRES is observed almost exclusively in conditions that cause systemic inflammation (e.g., autoimmune disorders, preeclampsia/ eclampsia, and sepsis), so another pathogenic theory suggests that a primary inflammatory insult involving T-cell activation, cytokine release, and leukocyte adhesion lead to endothelial dysfunction and BBB compromise [63]. A recent case-control study showed that symptomatic AIP patients have higher levels of several pro-inflammatory cytokines (e.g., IL-1b, IL-2, IL-6, IL-17, TNF, INF-γ) and vascular endothelial growth factor (VEGF) compared to matched healthy controls, which was partly attributed to porphyria-induced organ damage (e.g., the liver, kidney, nervous system, pancreas). These findings suggest that inflammation might have a role in the pathophysiology of AHP [84]. IL-17 and IL-2 stimulate macrophages to secrete TNF, IL-1b, and IL6, which along with INF-γ, induce the expression of adhesion molecules (e.g., intracellular adhesion molecule-1, vascular cell adhesion protein1, E-selectin, P-selectin). Adhesion molecules interact with leukocytes and stimulate reactive oxygen species (ROS) production. ALA and porphyrins also induce oxidative stress [85,86]. ROS and ALA may cause direct endothelial cell injuries [87]. TNF, IL-1b, and IL-6 promote the expression of VEGF, which weakens endothelial cell tight junctions and activates the vesiculo-vacuolar organelle, thus increasing vascular permeability. VEGF plasma levels in symptomatic AIP patients are up to 8.3-fold higher compared to matched healthy controls [84]. Additionally, pentraxin-3 (PTX3) plasma levels correlate positively with the biochemical activity of AIP after controlling for potential confounders and other inflammatory markers [84]. Similarly, PTX3 levels positively correlate with the severity of endothelial dysfunction in several diseases associated with PRES (e.g., preeclampsia, chronic kidney disease, and systemic lupus erythematosus) [88–90]. Experimental models in C57BL6 and FCγ receptor/P-selectin knockout mice have shown that PTX3 induces dysfunction and morphological changes in endothelial cells through several mechanisms [91]. Therefore, endothelial dysfunction due to immunological activation might be involved in the pathogenesis of PRES during porphyric attacks [92].

Reversible cerebral vasoconstriction was found in 41.7% of patients with PRES during porphyric attacks who underwent angiography, which is higher than previously reported in most series of PRES [1]. Ischemic lesions were identified in 19.6% of all patients and were the most common reason for incomplete radiologic recovery, as described in other studies [1]. This finding supports that porphyric attacks may lead to permanent brain damage with long-term consequences (e.g., cognitive impairment and focal neurological deficits), mainly explained by ischemic lesions, which reinforces the importance of early treatment on the chronic consequences of AHPs. PRES and porphyric attacks have been independently associated with arterial and arteriolar vasoconstriction, but the pathogenic mechanisms remain unclear. In both cases, they may include endothelial dysfunction, oxidative stress, and low nitric oxide levels [1,100]. Experimental studies have shown that ALA induces arteriolar vasoconstriction [101]. Increased adrenergic vasoconstriction and reduced cholinergic vasodilation responses have been demonstrated in mesenteric arteries of AIP mice, which are resolved after the administration of hemin [67]. Heme deficiency, high PTX3 levels, and ROS production during porphyric attacks may also contribute to vasoconstriction by impairing nitric oxide synthase function and nitric oxide bioavailability [91,102,103]. Furthermore, mitochondrial bioenergetic failure may contribute to vasoconstriction by increasing ROS formation and altering Ca++ homeostasis [93,104]. Finally, high levels of antidiuretic hormone (ADH) may stimulate vasoconstriction in patients with hyponatremia during porphyric attacks [105]. 4.7. Hyponatremia, antidiuretic hormone, and brain edema Although the incidence of hyponatremia in patients with PRES is unclear [2,80,106], numerous case reports have described an association between these conditions [107–109]. Hyponatremia is also found in 20–30% of patients with porphyric attacks, but it occurred about 2fold more frequently in AIP patients with PRES, suggesting a role for hyponatremia in the pathogenesis of cerebral edema during porphyric attacks. Hyponatremia produces an abnormal osmotic pressure gradient between the blood and interstitial fluid and cellular elements of the brain, which drive water into brain cells. Thus, it can contribute to cerebral edema and encephalopathy in the presence of factors that hinder brain adaptation capacity [e.g., acute starvation (< 48 h), estrogen, hypoxia, and/or increased ADH] [105]. 76.9% of patients with hyponatremia in this review were women in premenopausal ages. Porphyric attacks are more common in this population due in part to the inducing effect of estrogen and progesterone on ALAS1 [4]. PRES is also more common in women, even when patients with eclampsia are not considered, but to a lesser extent than porphyric attacks. Hyponatremia is usually acute during porphyric attacks. Cerebral hypoxia may also occur in patients with respiratory failure during porphyric attacks. Estrogens, ADH, hypoxia, mitochondrial bioenergetic failure, and ALA inhibit Na+/K+ ATPase, which impairs the capacity of glial cells to extract solutes and water from the brain and prevent cerebral edema [105,110]. Finally, the PEPT2 function can be reduced up to 59% at low sodium concentrations [83], which further decreases ALA brain efflux. Thus, patients with significant hyponatremia during porphyric attacks might have an increased risk of cerebral edema and encephalopathy. Hyponatremia is also a clearly defined cause of seizures, which emphasizes the importance of evaluating and managing this factor in

4.5. Mitochondrial dysfunction Mitochondrial bioenergetic failure may lead to neuromuscular alterations given the high energy demand of the nervous system and muscles [93]. A wide range of brain lesions is observed in MRI scans of patients affected by mitochondrial diseases, which sometimes resembles those of PRES [94,95]. In vitro and in vivo studies have shown that mitochondrial dysfunction is a frequent abnormality of AHP. Studies in cultured skin fibroblasts from AIP subjects with half-normal hydroxymethylbilane synthase revealed impaired mitochondrial NADH oxidation [96]. Altered mitochondrial oxidative phosphorylation and ATP production have also been demonstrated in the liver, muscle, and brain of AIP mice compared to wild-type mice [64,65]. In AHP subjects compared to matched healthy controls, mitochondrial stress tests have shown a decreased mitochondrial bioenergetic capacity, glycolytic function, and oxidative burst [97]. A significant inverse correlation between UPBG excretion and mitochondrial oxygen consumption has been observed as well [98]. Several mechanisms might explain the mitochondrial dysfunction during porphyric attacks. Heme deficiency can reduce enzymatic activities of respiratory chain complexes [64,65]. Also, cataplerosis of the tricarboxylic acid cycle with a low supply of reduced cofactors can occur due to the increased demand for succinylCoA for ALA synthesis by ALAS1 [64,65]. ALA can also directly damage 8

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Fig. 3. Concurrence of factors in the pathogenesis of PRES and CNS dysfunction during porphyric attacks.

data may have been described in the reports. Two articles only reported the diagnosis of PRES in head MRI scans without providing pictures or a detailed description of the main findings, so it was not possible to reassess the veracity of the diagnosis [38,44]. The same radiological techniques were not performed in all patients, so it is difficult to compare them and draw more general conclusions about neuroimaging during porphyric attacks. Besides, as PRES is a dynamic process, radiological findings may vary depending on when the study is done during the evolution of the syndrome. As ~30% of asymptomatic AHPs mutation carriers have a high UPBG (up to 15-fold ULN), misclassification may have occurred in patients in whom porphyric attacks were confirmed by UPBG < 15-fold or positive qualitative tests. However, characteristics of patients with UPBG≥15-fold and patients with UPBG < 15-fold or positive qualitative tests did not differ significantly. Finally, the proposed pathogenic model for PRES and CNS during porphyric attacks was constructed based on the comparison of abnormalities found in AHPs and other diseases frequently related to PRES and brain edema. Therefore, it is still necessary to performed studies directly in AHP patients or specific in vitro models of porphyria to reach definitive conclusions. Nevertheless, this model serves as a rational framework for those future investigations.

patients with porphyria attacks. Hyponatremia during porphyric attacks is sometimes the result of inappropriate secretion of ADH (SIADH). The hypersecretion of ADH may be due to ALA neurotoxicity in the hypothalamus, which is not protected by BBB [111]. Growing evidence indicates that IL-6 is a crucial regulator of ADH secretion by acting as an effector in areas of the brain that are involved in its release [112]. IL-6 activates the subfornical organ and the organum vasculosum of the lamina terminalis, thus leading to thirst and increased vasopressin secretion by neurons from the supraoptic nucleus and paraventricular nucleus. IL-6 serum levels also reflect disease activity in some autoimmune disorders that cause PRES, such as SLE [113]. In the case of SLE, serum IL-6 levels are significantly higher in patients with PRES than in those without PRES and healthy controls [114]. Similarly, IL-6 plasma levels in AIP patients have been found to be 2.5-fold higher than in controls [84]. However, the association between IL-6, ADH, and PRES during porphyric attacks still needs to be investigated. High ADH serum levels in AIP patients may also be an appropriate physiological response since decreased blood volumes have been demonstrated even without porphyric attacks [115]. Interestingly, when ADH monitoring was performed in an AIP patient with PRES during a porphyric attack, high ADH plasma levels were detected [57]. Similarly, high ADH levels have been described in other conditions associated with PRES (e.g., preeclampsia/eclampsia, chronic kidney disease, and anticancer drugs). Moreover, there is a significant overlap between some anticancer drugs associated with PRES and with SIADH. The use of desmopressin, a synthetic ADH analog, has also been associated with PRES [116]. ADH facilitates brain cells swelling through several mechanisms. It increases intracellular osmolarity by increasing the influx of Na+, K+, 2Cl- and reducing Na+ efflux. ADH also increases the free water influx through astrocytic aquaporin 4. Besides, the stimulation of V1a receptors leads to platelet aggregation, cerebral vasoconstriction and augmented sympathetic tone, producing endothelial dysfunction and cerebral ischemia. Cerebral ischemia stimulates overexpression of VEGF and increases endothelial permeability, which leads to vasogenic cerebral edema. In the periphery, stimulation of ADH receptors could contribute to some symptoms generally reported in PRES and porphyric attacks such as acute systemic arterial hypertension and renal failure [105,116].

6. Conclusions This systematic review shows that brain edema, vasoconstriction, and ischemia can explain the clinical manifestations of CNS dysfunction in some patients with porphyric attacks. Seizures, hyponatremia, and vasoconstriction seem to be more frequent in these patients than expected for either PRES or porphyric attacks, perhaps due to synergy between both conditions. Several porphyria-related abnormalities may lead to PRES or increase the risk of cerebral edema (e.g., systemic inflammation, ALA toxicity, mitochondrial dysfunction, hyponatremia, and antidiuretic hormone excess). However, the individual impact of each abnormality is probably small, since they are also observed in patients without central involvement, and differ among different abnormalities. The vulnerability to BBB compromise probably increases progressively as more abnormalities occur and begin to act synergistically. Therefore, the concurrence of multiple factors related to the porphyria, the patient, and certain precipitants is probably necessary (Fig. 3). Furthermore, patients with CNS dysfunction during attacks may develop long-term sequelae, such as cognitive decline and focal neurological deficits, which may likely be explained by ischemic lesions. A clearer definition of these pathophysiological phenomena will have a great impact on the management of patients with porphyria attacks. The next step for future research would be to assess the

5. Limitations This review has some limitations. Selection and publication bias is possible because reports of unusual forms of diseases are more likely to be published. Information bias is also possible as not all the essential 9

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incidence of PRES in patients with CNS dysfunction during porphyric attacks. Furthermore, comparing the prevalence of PEPT2 variants and levels of PTX3, IL6, nitric oxide metabolites, and ADH/copeptin in these patients versus those without CNS dysfunction or PRES during porphyric attacks.

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