|Year : 2020 | Volume
| Issue : 2 | Page : 78-83
Neurological manifestations of acute intermittent porphyria: Case series and current review
Rahi Kiran Bhattiprolu, Vijay Sardana
Department of Neurology, Government Medical College, Kota, Rajasthan, India
|Date of Submission||17-Feb-2020|
|Date of Acceptance||25-Apr-2020|
|Date of Web Publication||18-Jun-2020|
Rahi Kiran Bhattiprolu
Department of Neurology, Government Medical College, Kota, Rajasthan
Source of Support: None, Conflict of Interest: None
Background: Porphyrias are a group of inherited metabolic disorders, resulting from the deficiency of specific enzyme in the hemebiosynthesis. Among these, acute intermittent porphyria (AIP) is the most common type with neuropsychiatric features encountered in the clinical practice. In this study, we describe the presentation of AIP in five different patients admitted in our hospital. Materials and Methods: We prospectively collected the data of five patients of AIP admitted in our department in the past 2 years and studied in detail the causes, precipitants, clinical presentation, diagnosis, and management of AIP. Results: All five cases were males in second to third decades of life having a history of prior gastrointestinal symptoms for variable period before presenting to us with neurological manifestations of which one had abdominal pain for 2 years and had undergone appendicectomy also. All patients had seizures and psychiatric manifestations. Four patients had axonal polyneuropathy and respiratory failure requiring prolonged ventilator support. One patient had a past and family history of AIP. Sepsis as a trigger is noted in two patients. All patients had positive urine test for porphobilinogen. All had autonomic dysfunction, hyponatremia, and three patients expired after prolonged intensive care unit stay of which two had status epilepticus. Two patients survived with complete recovery and are under regular follow-up. Conclusion: Porphyria screening should be done in all patients presenting with unexplained motor neuropathy. Avoidance of triggers, early suspicion of the acute attack, and starting treatment immediately will prevent the complications and thus reduce morbidity and mortality due to the acute attack.
Keywords: Acute intermittent porphyria, axonal polyneuropathy, porphobilinogen, seizures
|How to cite this article:|
Bhattiprolu RK, Sardana V. Neurological manifestations of acute intermittent porphyria: Case series and current review. Apollo Med 2020;17:78-83
| Introduction|| |
Porphyrias are a group of eight panethnic-inherited metabolic disorders of hemebiosynthesis with each type, resulting from the deficiency of a specific enzyme in the hemebiosynthesis pathway. The terms porphyrin and porphyria are derived from the Greek word porphyrus, meaning purple as urine of these patients may be dark or reddish in color or may darken further after the exposure to light due to the presence of excess porphyrins and related substances. The Greeks borrowed the term from the Phoenicians, who extracted a purple pigment from purpura mollusks to dye the garments of their royal family.
The basis for the classification of porphyrias as either hepatic or erythropoietic is the accumulation of various types of heme precursors in either the liver or bone marrow, which are the tissues most active in heme biosynthesis. The major manifestations of the hepatic porphyrias are neurologic, including neuropathic abdominal pain, neuropathy, and mental disturbances. Among these, types with acute presentation and particular importance to neurologist are four according to the order of prevalence include acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and the extremely rare Doss porphyria. Among these, AIP is the most common acute type with neuropsychiatric features encountered in the clinical practice. In HCP and VP, acute attacks are less frequent and photocutaneous disease can be associated. The erythropoietic porphyrias mainly manifest with the skin findings without associated neurologic disease and will not be discussed in this review. In this study, we describe the presentation of AIP in five different patients admitted in our hospital and discuss in detail the causes, clinical presentation, diagnosis, and management of AIP.
Neurologic manifestations of porphyria were identified for over a century, initial case reports were described in 1890. The prevalence of the three most common porphyrias, porphyria cutanea tarda, AIP and erythropoietic protoporphyria is estimated to be 1 in 10,000, 1 in 20,000, and 1 in 50,000–75,000, respectively, in Europe. The annual incidence for symptomatic acute porphyria is 0.2/million (0.13/million for AIP and 0.08/million for VP and 0.02/million for HCP). AIP has been reported from many countries worldwide, but is especially common in Scandinavian countries and Great Britain. In a European 3-year prospective study, the prevalence of clinically overt AIP was 5.4 cases/million. The prevalence of mutations in the Western populations is approximately 1 carrier/2000 persons, but acute attacks occur in < 10%., This may indicate the role of environmental factors and genetic modifiers in triggering acute attacks. Due to a lack of large studies, the prevalence in India is not known. In the past, AIP has been reported from the various parts of India and was found with in some specific communities. In a study by Gauri et al. in 1990, 15 patients of AIP were detected out of 2,500 persons of the Maheshwari community surveyed in Sri-Dungargarh municipal area of Bikaner.
| Materials and Methods|| |
We are describing the neurological presentation and course of illness of five cases of AIP admitted in our department. All five cases are males in second-to-third decade of life out of which four cases presented to us 1–2 weeks after the onset of neurological symptoms in the form of areflexic flaccid quadriparesis, encephalopathy, and seizures [Table 1]. One patient had seizures and psychiatric symptoms without peripheral neuropathy. Only one patient had a past history of acute attack with complete recovery and the same patient had a similar history in his elder sister. All cases had gastrointestinal symptoms in the form of abdominal pain, vomiting, and constipation prior to neurological involvement. The time interval between gastrointestinal and neurological symptoms is variable. Sepsis as a trigger for acute attack could be identified in two patients. One patient had a prolonged history of abdominal pain of 2 years and he had undergone appendicectomy also.
All patients had positive qualitative test for PBG and quantitative analysis of urine PBG done in only two patients due to financial constraints was found to be elevated. Urine of all patients had color change on the exposure to sunlight. Status epilepticus occurred in three patients, and their EEG and CT head were normal initially. One patient had super refractory status epilepticus and subsequent EEG showed diffuse slowing. Seizures were treated with multiple anti-epileptic and anesthetic drugs [Table 1]. All patients had autonomic dysfunction, hyponatremia, four patients had areflexic flaccid quadriparesis with NCS showing axonal polyneuropathy and respiratory paralysis requiring prolonged mechanical ventilator support. Three patients expired after prolonged intensive care unit (ICU) stay of which two had Status epilepticus. Two patients survived with complete recovery and are under regular follow-up [Table 1].
| Discussion|| |
AIP has autosomal-dominant inheritance pattern with incomplete penetrance and is due to partial deficiency of the hydroxymethylbilane synthase, third enzyme in the heme biosynthesis. Only 10% of patients with mutation become symptomatic during their lifetime. It manifests with occasional neurovisceral crises due to the overproduction of porphyrin precursors such as porphobilinogen (PBG) and aminolaevulinic acid (ALA) which is released from the liver into the circulation. In 80%–90% of cases, acute attacks occur in women of reproductive age and are unusual before menarche and after menopause. In contrary to this, all our cases are males which may be a coincidental finding. The neurological manifestations of acute attack are variable, resemble acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and can easily be neglected. The estimated percentage of patients with AIP that will develop recurrent acute attacks was 3%–5%. As the mortality of an acute attack is ~10%, correct diagnosis and treatment during the early period of an acute attack are essential to avoid the worse outcomes.
Acute attack presents with varying combination of gastrointestinal, psychiatric, seizures, autonomic, and peripheral neuropathy. Triggers for acute attacks include many drugs (metabolized by Cytochrome P 450 oxidase), chemicals, alcohol, prolonged fasting, low glucose concentration, sepsis, oral contraceptives, and stress. The typical patient with an attack of AIP is a previously healthy young female with several days of severe fatigue and an inability to concentrate, followed by progressively worsening abdominal pain, nausea, vomiting, and neurologic signs (weakness, seizures, and altered sensorium).
This is the main reason for most of the clinical manifestations of acute attack. Autonomic neuropathy in AIP manifests as acute pandysautonomia with parasympathetic predominance. Abdominal pain is a hallmark of an acute attack, but the exact mechanism of pain is still not clear. Postulates includes splanchnic dysfunction leading to intestinal dilatation or spasm, local vasoconstriction and intestinal ischemia, enteric ganglionitis/ganglionopathy., These attacks typically present with severe pain, though generally there are no objective signs of an “acute abdomen.” Other autonomic features include tachycardia, hypertension, and bladder dysfunction. All our patients had pandysautonomia in the form of abdominal pain, tachycardia, and labile hypertension [Table 1].
At the beginning of an acute attack even before abdominal pain, anxiety and insomnia are usually present which might not be noticed by all caregivers. Hence, there may be wide variation in the occurrence of these symptoms in previous studies. PBG mimics the action of serotonin can act as a false neurotransmitter leading to psychiatric features. ALA which is structurally similar to gamma aminobutyric acid (GABA) may interact with the GABA receptor as a partial agonist, causing delirium and seizures. Mental syndrome of acute porphyria characterized by various psychiatric manifestations such as anxiety, restlessness, insomnia, depression, psychosis, aggressive, impulsive behavior with depressed mood, suicidal attempts, social withdrawal, auditory hallucinations, persecutory delusions, and catatonia occur during the acute attack. The most common psychiatric diagnosis in patients was generalized anxiety which was seen in three of our patients. The premorbid personality and mental health of patients between attacks seems normal. All our patients had anxiety, restlessness, insomnia, and one patient developed psychosis and irritability during hospital stay [Table 1].
Encephalopathy and seizures
Manifests with varying combination of headache, altered consciousness, or seizures in 20%–30% of patients. Acute encephalopathy can manifest as posterior reversible encephalopathy syndrome which may result from disrupted blood brain barrier due to the effect of toxins or fluctuating blood pressure. Seizures may be generalized or focal and seen in 2%–20% of the patients. Seizures can develop because of hyponatremia or hypomagnesemia or as a manifestation of porphyria. Three of four patients had status epilepticus refractory to medicines and two of those patients did not survive. Hyponatremia develops in 40% of cases which may occur due to syndrome of inappropriate anti diuretic hormone secretion (SIADH), dehydration or primary renal tubular defect leading to dehydration. All our patients had hyponatremia which was corrected accordingly [Table 1].
Acute peripheral neuropathy
Acute peripheral neuropathy is the most common neurological complication of a severe acute attack. It manifests as quadriparesis with hypo to areflexia and predominant proximal and upper limb weakness which may lead to respiratory failure due to diaphragmatic paresis. Ankle jerk may be preserved. Sensory symptoms may be seen but objective sensory loss is less common. Cranial nerve involvement, commonly third, fourth, ninth, and tenth is seen in 35%–55% patients. The routine examination of cerebrospinal fluid will be normal, indicating the absence of neuroinflammatory process in the central nervous system and the proximal nerves. Nerve conduction studies are suggestive of axonal type with or without secondary demyelination, if present indicate more severe attack. Some patients rapidly recover, suggesting a reversible acute toxic-metabolic neuronal injury. Those with fixed weakness caused by axonal degeneration improve slowly (mean time to recovery, 10.6 months for proximal muscles, and nearly twice as long for distal muscles). Four of four patients had axonal polyneuropathy, of which one surviving patient improved completely in 6 months [Table 1].
The course of an acute attack is probably directly related to the permeability of blood-brain and blood-nerve barriers to porphyrin precursors, which are small size molecules. The absence of a barrier for autonomic nerves and a sparse blood-brain barrier in hypothalamus and limbic areas may explain initial manifestations such as dysautonomia and mild mental changes in an acute attack. When the excess of ALA proceeds and the barrier function is disrupted, peripheral neuropathy and severe encephalopathy will develop.
The occurrence of acute attacks is unusual before menarche and after menopause. In women with AIP, attacks sometimes occur regularly in the luteal phase of the menstrual cycle related to the surge in the progesterone level.
Various atypical manifestations of AIP, mentioned previously in case reports include mononeuritis multiplex, focal motor neuropathy, pseudo myasthenia, bilateral radial neuropathy, and subarachnoid hemorrhage.
The secondary causes of porphyria should be ruled out which includes alcohol, lead toxicity, hexachlorobenzene, and heriditary tyrosinemia.
Late complications in acute porphyria
There is long-term risk of carcinogenesis, especially hepatocellular carcinoma. In a review of 82 deceased adult Finnish patients with acute hepatic porphyria it was found that the cause of death in seven was hepatocellular carcinoma which was much higher than that of the general population.
Patients also may develop sustained hypertension, chronic kidney disease due to vascular toxicity of porphyrin metabolites and chronic pain poorly responsive to hemin and opiates as the late complications.
The diagnosis of porphyria can be challenging unless a high index of clinical suspicion is present. The most commonfirst-line screening test is urine analysis for PBG excretion. First test the change in color of urine on the exposure to the sunlight due to presence of photosensitive pigments. If this test is positive samples of urine, faces and serum can be estimated for PBG levels, both qualitative and quantitative. There is little relationship between the severity of neurological manifestations and ALA and PBG levels. These levels will be elevated in AIP for longer duration than other acute types. All our patients had change in color of urine on exposure to sunlight and elevated urine PBG levels [Table 1]. High-performance liquid chromatography can be used to separate different patterns of porphyrins in urine, feces, and plasma. Various relevant enzymes can also be assayed in cytoplasm and mitochondria. In AIP, PBG-D level is usually reduced to 50% of normal. Enzyme assays may mislead and should not be used in place of porphyrin analysis.
Due to variable neurological manifestations, AIP has many differential diagnoses. They include AIDP, multifocal motor neuropathy, chronic inflammatory demyelinating polyradiculoneuropathy and POEMS syndrome, lead poisoning, acute presentations of neuromuscular junction disorders such as myasthenia gravis or toxic myopathies, lyme disease, west nile virus, enterovirus, and herpesvirus.
The most important management strategy in patients with porphyria is the prevention of acute attacks or treat the acute attack as early as possible before the onset of neuropathy and respiratory failure.
Treatment of the acute attack
First, remove all offending drugs and treat intercurrent infection. A high-carbohydrate diet orally or by nasogastric feeding at a dose of 400 g daily or the equivalence of glucose results in reduced porphyrin precursor production. Persistent symptoms or neurological deficits that progress for 24 h after carbohydrate loading are indications for treatment with hematin which represses the activity of hepatic ALA synthase and may restore cytochrome functions by replenishing an endogenous heme deficit. Hematin therapy at the recommended dose of 6 infusions of 4 mg/kg body weight at 12-h intervals has resulted in consistent reduction of porphyrin precursors in serum and urine over 2–3 days and clinical improvement in more than 80% of attacks. Early administration of hematin is advocated to correct the metabolic insult before neuronal damage becomes irreversible. Due to its cost and lack of availability in India, our patients were treated with intravenous glucose and other supportive therapy. As the cases presented to us few weeks after the onset of neurological symptoms, only two out of five patients could recover after prolonged ICU stay. Use drugs with caution and avoid drugs metabolized by cytochrome pathway. Opioids for pain, beta blockers for tachycardia, oral gabapentin, intravenous diazepam, parental magnesium sulfate, propofol, and ketamine can be used for seizure control can be used. In women with attacks related to menstruation, suppressing ovulation with the luteinizing hormone-releasing hormone analog, buserelin, has been shown to reduce the number of attacks.
Prevention of attacks
Patients who have had attacks of porphyria should be advised about triggers of acute attacks, their prevention and importance of maintaining a high carbohydrate diet.
Counselling of patients and carriers
Currently, it is unknown what proportion of asymptomatic carriers go on to develop acute attacks. Hence, wherever possible identification of carriers in the family by genetic testing should be undertaken as biochemical methods lack sensitivity and specificity for testing relatives. Contraception should be discussed with women and the risk of oral and depot hormonal contraception should be explained. Many porphyria specialists recommend the intrauterine device. Both patient and family should be advised about the triggers of acute attacks and their prevention.
| Conclusion|| |
All our patients presented with gastrointestinal and neurological manifestations which may vary widely. Hence, porphyria screening should be done in all patients presenting with unexplained motor neuropathy with one of the additional features discussed above. It is also important to screen the family to avoid unnecessary exposure to potentially dangerous drugs. As the only approved treatment hemin is costly and not readily available in India, current research focused on developing gene and stem cell replacement, pharmacologic chaperones to rescue misfolded mutant enzymes and transplantation of hepatic or erythroid derived corrected pleuripotent stem cells may change the treatment perspective in future. This article highlights the fact that avoidance of triggers, early suspicion of the acute attack, and starting treatment immediately will prevent the complications and thus reduce morbidity and mortality due to the acute attack.
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Conflicts of interest
There are no conflicts of interest.
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