Porphyria is a collective name of seven different diseases that are caused by an enzyme deficiency that inhibits the synthesis of heme. AIP is one of four forms of acute porphyria, which is caused by an inherited deficiency of PBGD. Symptoms of AIP occur during intermittent attacks are caused by the excess production of porphyrin precursors in the visceral, peripheral, autonomic, and central nervous systems, and may be life threatening.
Neurological manifestations of AIP include epileptic seizures, impaired consciousness, behavioral changes and hyponatremia maybe caused by inappropriate antidiuretic hormone syndrome [7, 8]. Peking union medical college hospital reported the characteristics of 36 Chinese patients with acute porphyria in 2016; 12 patients experienced neurological symptoms involving the CNS (12/36 confusion, 10/36 convulsion, 2/36 rapid progression to acute respiratory insufficiency)[7]. The prodromal symptoms in these cases included abdominal pain, muscle weakness. The weakness in case 9 and 15 progressed rapidly to quadriparesis and acute respiratory insufficiency, resulting in the delayed diagnosis.
The pathophysiology of the nervous system involvement of AIP patients is not very clear. Most reports of the neurological manifestations and brain imaging findings of AIP have been restricted to a single or small number of cases[8–10]. In vivo studies in mice have suggested that multiple mechanisms leading to the varied symptoms, including interactions between 5-Aminolevulinic acid (ALA) and gamma-Aminobutyric acid (GABA) receptors and possibly heme depletion in nerve cells[9]. However, some findings in AIP patients have suggested that the relationship between the severity of neurological manifestations and the ALA/PBG levels is little[10]. In mainland China, tests of ALA and PBG levels are unavailable, it had been found that the serum sodium concentration was significantly negatively correlated with convulsion in our clinical studies[7]. These findings may reveal many factors contributing to the neurological manifestations of AIP. In 2011, the Chang Gung Memorial Hospital in Taiwan reported 12 cases of AIP; 9 patients experienced neurological symptoms involving the CNS (8 consciousness disturbance, 4 convulsion/seizure, 1 behavioral change). Among 4 patients who underwent brain MRI, 3 showed normal results, and 1 showed PRES, and this lesion recovered after 1 year[10]. In our study, 29 patients experienced CNS neurological symptoms, among 20 patients who underwent MRI, 9 showed MRI abnormality (2 PRES,4 ODS, 3 porphyric encephalopathy,1 RESLES).
The porphynic encephalopathy are believed to be most likely due to transient ischemic cerebral changes, although specific mechanism is unknown[11, 12]. These porphynic encephalopathy showed cortical and subcortical increased signal and gyriform diffuse enhancement[11–13].Our case 6 and 8 (Fig. 1) had similar cerebral abnormalities, case 8 had been followed by 3 MRI though 10 mons, showed consistent cerebral abnormalities, case 6 wasn’t followed up.
Even though there are only a handful of PRES has been reported in AIP patients, it is by far the most common MRI abnormalities in AIP[3, 4, 9, 10]. In these cases, transient changes were observed in the cerebral cortex on MRI. Usually, these lesions are partially or completely reversible, symmetrical cortical and subcortical involvements of the occipital and parietal lobes, without or with mild enhancement, as observed in case 20 (Fig. 3). The most widely accepted hypothesis of the pathophysiology of PRES is the hyperperfusion theory[14]. The mechanism of PRES in AIP has been suggested to be mediated by hypertension due to autonomic dysfunction[5]. Case 20 progressed to dysphoria, confusion and severe hyponatremia after being diagnosed with “pregnancy-induced hypertension.” However, our first patient with PRES in AIP (case 9) remained normotensive throughout, but she also had severe hyponatremia. Cases of PRES secondary to hyponatremia are rare in the literature[5, 15], little is known about the influence of hyponatremia on cerebrovascular regulation.
ODS refers to central pontine myelinolysis and extrapontine myelinolysis. These disorders are characterized by insults to regions of the brain with anatomical features predisposing white matter tracts to myelin injury in the setting of osmotic disturbances and their attempted correction[16]. Although many AIP patients have hyponatremia[7], ODS in AIP has been rarely previously reported[13]. Case 2,5,16 and 27 are first reported cases of AIP with ODS in China. These two patients had severe hyponatremia, which was quickly corrected before she experienced confusion or frequent convulsion. After three weeks, MRI of case 5 showed typical central pontine myelinolysis and extrapontine myelinolysis, as shown in Fig. 2. The clinical outcome of ODS was thought to be universally devastating[16], but case 5 completely recovered, and the MRI lesions regressed (Fig. 2). The MRI lesions of case 2 after 2 weeks no changed to the first time.
All 29 cases we reported showed severe hyponatremia, and it was found that the serum sodium concentration was significantly negatively correlated with convulsion before[7]. Blood sodium levels of who with MRI/CT abnormality were significantly lower than which with normal MRI/CT(110 ± 43.15 mmol/L and 117 ± 57.02 mmol/L, p = 0.01).We suggest that hyponatremia may be not only a clinical feature of AIP but also an important mechanism in porphyric encephalopathy. An increase in vasopressin levels occurs in hyponatremia[5]. Vasopressin facilitates the movement of water molecules into cerebral cells independently of hyponatremia by reducing the use of cerebral oxygen. Hyponatremia therefore plays an important role in cerebral edema. More research is needed in the future to prove this hypothesis. Because hyponatremia is a common feature in AIP, the rapid correction of hyponatremia should be avoided to prevent ODS.