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Home , Erythropoietic porphyria, Hepatic porphyria, Porphyria, Porphyria cutanea tarda, Variegate porphyria

Journal ofNeurology, Neurosurgery, and Psychiatry 1997;62:319-328 319

REVIEW J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.62.4.319 on 1 April 1997. Downloaded from

The little imitator-: a neuropsychiatric disorder

Helen L Crimlisk

Abstract Porphyria is derived from the Greek word por- Three common subtypes of porphyria phuros meaning purple. Protoporphyrin IX is give rise to neuropsychiatric disorders; the biologically active substance, an important acute intermittent porphyria, variegate feature of which is its metal binding capacity. porphyria, and coproporphyria. The sec- Both chlorophyll and haem are metallopor- ond two also give rise to cutaneous symp- phyrins and are involved in the processes of toms. Neurological or psychiatric energy capture and utilisation in animals and symptoms occur in most acute attacks, plants. The description of the by and may mimc many other disorders. Nobel laureate Hans Fischer' in 1930 as: The diagnosis may be missed because it is "The compounds which make grass green not even considered or because of techni- and red." cal problems, such as sample collection indicates the central position of these sub- and storage, and interpretation of results. stances in the biological sciences. A negative screening test does not exclude The are a heterogeneous group the diagnosis. Porphyria may be overrep- of overproduction , resulting from resented in psychiatric populations, but genetically determined, partial deficiencies in the lack of control groups makes this haem biosynthetic . Their manifesta- Department of uncertain. The management of patients tions are broad and their relevance in neu- Neuropsychiatry, with porphyria and psychiatric symptoms ropsychiatric disorders may sometimes be Institute ofNeurology, causes considerable Queen Square, problems. Three overlooked.2 Indeed, porphyria was described London, UK cases are described to illustrate some of by Waldenstr6m3 as the "the little imitator," H L Crimnlisk these issues. Advances in molecular biol- by contrast with , "the big imitator" of Address for correspondence: ogy permit identification of patients and the 20th century. is confus- Dr Helen L Crimlisk, early Terminology Neuropsychiatry Group, latent carriers in the family. Care to avoid ing and they have been categorised in several Department of Clinical relapses and improved treatments have different ways: as acute, non-acute, hepatic,

Neurology, Institute of http://jnnp.bmj.com/ , Queen Square, reduced the mortality. cutaneous, and neurovisceral, among others. London WC1N 3BG. The most useful clinical categorisation is Received 25 June 1996 (3 Neurol Neurosurg Psychiatry 1997;62:319-328) based on symptoms and divides the and in final revised form (table 1), 18 December 1996 into cutaneous, neuropsychiatric, and Accepted 8 January 1997 Keywords: porphyria; ; metalloporphyrins mixed disorders. on October 1, 2021 by guest. Protected copyright. Table 1 Biochemistry ofthe porphyrias (neuropsychiatric involvement in bold) Pathway Disorder Inheritance Neuropsychiatric Cutaneous Glycine + succinyl-CoA * ALA synthetase 5-aminolaevulinic acid (ALA) * ALA dehydratase Plumboporphyria Autosomal + + + 0 recessive (PBG) * PBG deaminase Acute intermittent porphyria Autosomal + ++ 0 dominant Hydroxymethylbilane * Uroporphyrinogen synthetase Congenital erythropoietic Autosomal 0 + + + Uroporphyrinogen m (URO) porphyria recessive * Uroporphyrinogen oxidase Autosomal 0 + + + dominant (20%) or acquired Coproporphyrinogen m (COPRO) * Coproporphyrinogen oxidase Hereditary coproporphyria Autosomal + + + + dominant Protoporphyrinogen IX (PROTO) * Protoporphyrinogen oxidase Autosomal + + + + + dominant Protoporphyrin IX * Erythropoietic protoporphyria Autosomal 0 + + + haem dominant 320 Crimlisk

Most porphyrins are inborn errors of result of the hypothesis of McAlpine and

, but some-for example, por- Hunter'5 that George III's frequent bouts of J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.62.4.319 on 1 April 1997. Downloaded from phyria cutanea tarda-may be acquired. The insanity were due to porphyria, although this neuropsychiatric porphyrias (for example, view is still controversial.'6 17 Porphyria has acute intermittent porphyria) and the mixed also been implicated in van Gogh's illness'8 porphyrias (for example, variegate porphyria and in the obstetric history of Queen Anne.'9 and hereditary coproporphyria) may give rise Waldenstrom in Sweden20 and Dean in to acute, potentially fatal, neurovisceral crises, South Africa'" have commented on the rarity with neuropathy, delirium, psychosis, auto- of manifest porphyria before the introduction nomic instability, and . of porphyrinogenic drugs such as Variegate porphyria and hereditary copropor- and sulphonamides. In South Africa, where phyria also cause dermatological features, usu- the 20 original Free Burghers have multiplied ally in the form of a bullous or erythematous 12 500 fold since the 17th century, this auto- . Plumboporphyria has only been somal dominant condition did not confer life described in a few cases but resembles acute threatening disadvantages on people with the intermittent porphyria clinically. Other condi- genotype. The widespread use of potentially tions such as hereditary tyrosinaemia and lead porphyrinogenic drugs and greater poisoning may produce secondary abnormali- consumption may have led to increased clini- ties of metabolism with similar clin- cal manifestation of the underlying genetic ical and biochemical features. defect.7 Eighty per cent of patients who have inher- ited haem biosynthetic enzyme deficiencies never develop symptomatic disease and are Epidemiology thought to be "latent porphyrics".4 Relatively The estimated frequency of acute inter- little progress has been made in predicting mittent porphyria is 1-2 in 10 00020; however, who will develop clinical features,5 although there is great regional variability. The preva- women seem to be at much greater risk than lence of variegate porphyria among the men. The characterisation of individual molec- Afrikaans population of South Africa, where ular defects in the encoding the haem the introduction of the disorder has been biosynthetic enzymes has led to the identifica- traced back to a Dutch immigrant in 1688,'3 is tion of homozygous forms-for example, 1 in 250. The resultant high awareness of var- harderoporphyria, the homozygous form of iegate porphyria may have resulted in an coproporphyria.6 These are often associated underestimate of the importance of acute with more florid clinical features. intermittent porphyria.'6 Other than in South Recent developments in molecular Africa, acute intermittent porphyria seems to make the accurate diagnosis of porphyria pos- be the most common, with ratios of acute sible in the proband as well as allowing genetic intermittent porphyria:variegate porphyria: counselling and screening in family members. hereditary coproporphyria of 100:15:7 in Appropriate advice on avoiding potentially Germany2' and 100:50:26 in Czechoslovakia.22 porphyrinogenic drugs has been shown to In addition to the three autosomal dominant reduce the incidence of attacks.7 The preva- subtypes of porphyria mentioned above, lence of the phenotype may be increasing,7 plumboporphyria, an autosomal recessive con- making detection of apparently latent carriers dition which presents with neuropsychiatric http://jnnp.bmj.com/ more important. Whereas advances have been symptoms, has been described in six cases made in the diagnostic tests available, pitfalls worldwide23 and a localised cluster of cases, in diagnosis are still common8 resulting in the known as "Dobson's complaint" (a combina- false belief that "porphyria has been tion of the enzyme deficits responsible for excluded". Finally, a recent family study9 acute intermittent porphyria and variegate found a higher incidence of generalised anxi- porphyria with a similar clinical picture) has been described in Cheshire, UK.24 An out- ety disorder in "latent" relatives of patients on October 1, 2021 by guest. Protected copyright. with acute intermittent porphyria, raising break of "secondary porphyria" occurred in doubts as to the relation between phenotype Turkey after the exposure of 4000 people to a and genotype in so-called "latent" carriers. fungicide, hexachorobenzene, resulting in a mixed porphyric picture in many people as well as the death of many infants through Historical aspects breast milk transmission.25 Porphyria is less The first description of acute porphyria as a common before adolescence and after the clinical syndrome was in 1889 by Stokvis.'° menopause, and symptomatic cases are four The attack occurred after the administration times more common in women, with a particu- of sulphonal, a drug which had been intro- lar preponderance premenstrually.26 duced as a hypnotic a year earlier. Congenital Waldenstrbm'2 first showed the presence of was recognised as an excess porphyrin metabolites in asymptomatic inborn error of metabolism by Garrod in relatives of patients with acute intermittent 1923.1" Important work on the description of porphyria and proposed the now accepted the clinical condition originated in areas where hypothesis of autosomal with vari- the incidence of porphyria was high-for able penetrance. Mustajoki and Koskelo27 example, acute intermittent porphyria in measured porphobilinogen deaminase (PGB- Sweden'2 and variegate porphyria in Cape D) activity in healthy Finnish blood donors in Town.'3 14 Porphyria has become topical in the an attempt to calculate the prevalence of the in the past few decades as a genotype in the population. They found The litde imitator-porphyria: a neuropsychiatric disorder 321

unequivocally low values in 0A4% and border- cific, with different genes encoding both

line concentrations in a further 0-4%, suggest- and erythroid isoenzymes. Thus the hepatic J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.62.4.319 on 1 April 1997. Downloaded from ing a high rate of latent carriers. Thus the isoenzyme of ALA is inducible when demand frequency of the responsible genes in the popu- for haem rises but the erythroid isoenzyme is lation is high and more than 80% of those who produced to subserve the more constant inherit the genetic defect do not develop demand for haemoglobin synthesis. Hepatic symptoms.4 haem is under negative feedback The prevalence of porphyria in psychiatric through the activity of ALA synthase. Enzyme populations was first investigated by Kaelbling turnover is high, which permits rapid adjust- et al,28 who found that 35 of 2500 psychiatric ment.33 Feedback can be mediated at the patients admitted to a short term intensive stages of transcription and transport into mito- care psychiatric unit had a positive screening chondria, as well as by post-translational activ- Watson-Schwarz reaction. Twelve of these ity of the enzyme itself. The system is were considered to have manifest acute inter- exquisitely sensitive to rapid oscillations in mittent porphyria on clinical grounds (point haem demand.23 prevalence 0 48%). A similar study in In the porphyrias, a partial enzyme defi- Australia,29 using quantitative PBG analysis ciency leads to overproduction of precursors alone, found a prevalence of 0O16%. The such as ALA and PBG, which may induce the results of these earlier studies can be criticised clinical picture by acting as false neurotrans- because of the use of a single test, which is mitters. Alternatively, the clinical picture may now known to have a high rate of false positive be caused by haem deficiency.34 The recent and false negative results.30 Tishler et al development of a mouse model for acute inter- screened nearly 4000 psychiatric inpatients mittent porphyria35 should help to resolve this and calculated a point prevalence of 0-21%. In issue. Table 1 shows the biosynthetic pathway this study, screening was based initially on the for haem with the porphyria subtypes caused Watson-Schwartz reaction, with 24 hour by enzyme deficiency along this pathway. analysis of 5-aminolaevulinic acid (ALA) and Secondary porphyria results in a similar bio- porphobilinogen (PBG) in those with a posi- chemical and clinical picture to the mixed por- tive result. Of the 70 who screened positive, phyrias. The exclusion of toxins-for example, eight were thought to have manifest acute alcohol, lead or hexachlorobenzene-as a intermittent porphyria on the basis of further cause is important. Hereditary tyrosinaemia tests, including assay of the enzyme PBG type 1, due to a partial deficiency of the deaminase. In a further 10 positive patients, enzyme fumaryl acetoacetate hydrolyase, acute intermittent porphyria was thought not results in a secondary deficit of ALA dehy- to be aetiologically related to their symptoms, dratase, causing a similar clinical and bio- despite abnormal enzyme concentrations, chemical picture to plumboporphyria.'6 Lead because of the absence of raised urinary por- inhibits ALA dehydratase, as well as several phyrin precursors. Most of the patients other enzymes in the haem biosynthetic path- described in these studies had diagnoses of way and may produce both an acute crisis as schizophrenia, schizoaffective disorder, or well as a chronic neuropathy with intellectual atypical psychoses. decline and other mental changes.37 These estimates seem to represent an increased prevalence of both latent and mani- http://jnnp.bmj.com/ fest porphyria in psychiatric populations. Pathogenesis However, there are significant methodological Both neurological and gastrointestinal symp- problems with the studies to date; in particu- toms are thought to result from neuronal dys- lar, given the wide geographical variability, the function. Histological findings in peripheral absence of control groups. It remains unclear and autonomic nerves include oedema, irregu- whether porphyria was causally related to the larity of the myelin sheaths, thinned and

psychiatric disorder seen. An alternative expla- irregular axons, axonal vacuolisation, and on October 1, 2021 by guest. Protected copyright. nation is that porphyria modifies an already degeneration and cellular infiltration.'8 present psychiatric disorder in a way which Electrophysiology shows muscle denervation makes patients more likely to be admitted to and decreased motor nerve conduction veloci- hospital, such as by worsening symptoms or ties.'9 The pathogenesis of the cerebral mani- inducing apparent "drug resistant" or refrac- festations, however, remains unclear. The tory cases. Equally, no systematic follow up main hypotheses are metabolic abnormalities, studies have been performed on the effect of ischaemia, demyelination, and oxidative stress. removing porphyrinogenic agents from such Pathology of the CNS includes vacuolisation patients' medication regimens, although case of neurons, focal perivascular demyelination, reports suggest that early improvements may and reactive glial proliferation.40 Unfor- occur.31 32 tunately, postmortem pathological findings bear little relation to the clinical features in life, supporting the theory that many of the Biochemistry clinical features may be caused by profound The haem biosynthetic pathway is tightly con- metabolic abnormalities. trolled by several mechanisms allowing rapid One hypothesis is that ALA may disturb adjustment when demand for haem, the end neurophysiological mechanisms through its product, changes. The first enzyme in the structural similarity to y-aminobutyric acid pathway, ALA synthase, is an important part (GABA).41 Others have proposed that multifo- of this regulation and seems to be tissue spe- cal ischaemia is responsible, through vaso- 322 Crimlisk

spasm. Black et al42 showed reversible angio- thromycin, sedatives such as barbiturates, ben-

graphic changes, indicating arterial vasospasm zodiazepines and sulpiride, hormone products J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.62.4.319 on 1 April 1997. Downloaded from in porphyric encephalopathy. King and such as the oral contraceptives, anabolic Bragdon43 described the MRI findings in a 20 steroids, hormone replacement therapy and year old woman with an acute, drug induced , antiepileptics such as attack of acute intermittent porphyria charac- and , drugs of abuse including terised by abdominal pain, , visual hal- and amphetamines, as well as many lucinations, lethargy, and . On the commonly prescribed drugs such as antihista- eighth day MRI showed multiple high signal mines, diuretics, baclofen, metoclopramide, intensity lesions, predominantly in frontal and many of the tricyclic , and parietal lobes. When she was asymptomatic 10 diclofenac. Table 2 shows a list of drugs which days after treatment, the lesions had resolved. are generally thought to be safe and can be Thunell et al44 proposed that oxidative stress used in the treatment of an acute porphyric was important in the clinical manifestations attack. and free radical formation may contribute to Alcohol has long been noted to precipitate the sometimes irreversible pathological acute attacks of porphyria in some patients. changes.40 Complement activation and media- Ethanol, although a good inducer of the tors of have also been impli- P-450 system in vitro, it is a less cated.45 In variegate porphyria and hereditary potent inducer in intact rats.50 In , coproporphyria, free radicals produced by the there is wide variability in alcohol tolerance absorption of solar energy result in among porphyric patients.5' The evidence that or bullous lesions.23 histology is charac- alcohol itself is porphyrinogenic is conflicting. terised by homogeneous PAS positive thicken- Thunell et a150 failed to show a relation ing and IgG deposition in vessel walls. between the amount of alcohol consumed, or the frequency of ingestion and the develop- ment of porphyric symptoms in acute inter- Precipitating agents mittent porphyria. The intake of some A partial deficiency in one of the enzymes of alcoholic beverages, especially red wine and haem biosynthesis is not usually sufficient to whisky, was significantly related to symptoms. result in the clinical syndrome. Many people They proposed that long chain alcohols and with the genetic abnormality never develop polyphenolic compounds such as tannins were symptoms, despite exposure to high doses of responsible for inducing porphyric attacks porphyrinogenic agents, and it is likely that rather than ethanol itself. there are other factors which modify the Starvation may induce the activity of response of the body. Most of the agents hepatic ALA synthase, an effect which is over- which predispose to the clinical picture of por- come by the administration of . Thus phyria deplete intracellular haem, which is dieting and eating disorders may precipitate an thought to be due to increased production of acute attack. The mechanism of this effect is the haemoprotein cytochrome P-450. This uncertain, but calorie restriction has been may be caused by induction of the cytochrome shown to be associated with a significant rise P-450 enzyme system, depletion of free haem in urinary excretion of ALA and PBG, which due to direct inhibition of its synthesis, or is reversed by increased carbohydrate intake.52 direct degradation of haem.46 Glucose may inhibit ALA synthase.23 http://jnnp.bmj.com/ Many patients presenting with acute attacks Oestrogen and progesterone aggravate por- have ingested a known porphyrinogenic drug phyria52 and cyclic attacks most commonly which could account for the attack.47 A com- occur in the luteal phase. The relation mittee has been set up to compile a database between cigarette and recurrent on the porphyrinogenicity of drugs.48 The cur- attacks may be due to metabolic induction of rent list of drugs thought to be porphyrino- haem.53 The claim that stress, surgery, and are has not been genic is long and details can be found in the infection precipitants sup- on October 1, 2021 by guest. Protected copyright. British National Formulary49 or obtained from ported by published data. Acute porphyria was the Porphyria Research Group in Cardiff previously thought to be rare before adoles- (Porphyria Research Unit, Department of cence, possibly because children are less likely Medical Biochemistry, Heath Park, Cardiff to be exposed to precipitants such as drugs or CF4 4XN, UK). Common culprits include alcohol. There are recent reports of acute such as sulphonamides and, ery- attacks in children, often related to the use of potentially porphyrinogenic medication.54-56

Table 2 Drugs probably safe in porphyria Clinical manifestations Symptoms Safe treatment options The clinical manifestations of the porphyrias Pain Narcotics-for example, codeine, are variable and the potential for misdiagnosis Paracetamol, aspirin is / Propranolol great (table 3).125759 Anxiety/sleeplessness Propranolol, lorazepam, chloral hydrate In patients with recognised acute attacks, Nausea/ , promazine, cyclizine the and mental health Delirium/psychosis -for example, chlorpromazine, premorbid personality trifluoperazine, droperidol of patients between attacks seems normal.60 Seizures Lorazepam, paraldehyde, bromides, course be chronic or acute on The clinical may Depression Lofepramine chronic,6' and episodes may be self limiting or Infection Penicillins, aminoglycosides progressive. The variability of the clinical Lactulose, neostigmine course as well as the episodic nature and The little imitator-porphyria: a neuropsychiatric disorder 323

Table 3 in acute porphyria (most data refer to acute intermittent seizures occur in nearly a quarter of cases. porphyria) Autonomical neuropathy is responsible for J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.62.4.319 on 1 April 1997. Downloaded from Percentage ofcases many of the systemic features of acute por- Stein and Mustajoki and phyria including abdominal pain, vomiting, Waldenstrom Goldberg Tschudy Nordmann constipation, hypertension, and tachycardia. 195712 1959¶7 197058 199359 Signs and symptoms n = 321 n = 50 n = 46 n =51 Abnormal autonomic cardiac reflexes have been shown to occur during an attack, but Abdominal pain 85 94 95 96 Mental symptoms 55 58 40 19 regress on remission66 and abnormal gastroin- Constipation 48 84 48 78 testinal mobility has also been found.67 Pain elsewhere - 52 50 25 Vomiting 59 88 43 84 Seizures may be focal or generalised and may Muscle weakness 42 68 60 8 rarely be the presenting feature of porphyria.68 Hypertension 40 54 36 57 Tachycardia 28 64 80 79 A recent epidemiological survey found that 37 14 9 - seizures are less common than previously Respiratory 14 10 9 - Convulsions 10 16 20 1 thought, with a lifetime prevalence of 5 1% Sensory loss 9 38 26 - among patients with manifest acute intermit- tent porphyria and 2-2% of all those with the genotype.69 In the United Kingdom, 75% of bizarre features mean that porphyria may go cases of variegate porphyria have skin lesions undiagnosed and be put down to somatisation, alone, the remainder dividing equally between conversion disorder, or to other psychiatric mixed and neuropsychiatric alone. In heredi- disorders. Several authors have described tary coproporphyria, skin lesions alone are patients long incarcerated in mental hospitals uncommon. Cutaneous features in variegate who are eventually diagnosed with por- porphyria and hereditary coproporphyria com- phyria,586162 although there are no reports on prise photosensitivity, skin fragility, bullous the outcome of these patients. lesions, facial , and hyperpig- Of the 29 attacks in 25 patients analysed by mentation in addition to the neuropsychiatric Ridley,38 10 patients died. Sudden death sug- features, which are otherwise indistinguishable gesting cardiac arrythmias was the most com- from those of acute intermittent porphyria. mon cause of death. Later studies have shown lower mortality rates. Kauppinen and Mustajoki,63 analysing their series of 206 Psychiatric symptoms patients, found that both the mortality associ- Most of the larger case series have been under- ated with attacks and the risk of further attacks taken by neurologists or physicians, thus has greatly reduced over time, commensurate "mental symptoms" are not fully characterised with better recognition, improved treatment and their incidence is likely to have been regimens, and counselling of patients to pre- underestimated. Anxiety, restlessness, insom- vent risk taking behaviour. Their group has nia, and depression and psychosis occur often also confirmed findings by Hardell64 showing and may be persisting features.23 Detailed psy- an increased incidence of hepatocellular carci- chiatric assessment has been limited to small noma (which accounted for 8-3% of deaths in series or case reports. In one family, acute their porphyric patients) and chronic renal attacks of acute intermittent porphyria pre- failure (which accounted for 4% of deaths). In sented as aggressive, impulsive behaviour with patients who survive a severe acute attack, depressed mood and suicidal attempts.32 http://jnnp.bmj.com/ complete recovery is the rule, although recovery Others have described schizophrenic symp- may be protracted. Distal weakness and sen- toms such as social withdrawal, auditory hallu- sory loss are the most persistent features. cinations, persecutory delusions, and catatonia31; affective symptoms with emotional lability, insomnia and grandiose delusions; Physical symptoms and signs and conduct disorder with disruptive behav-

The neuropathy in porphyria is primarily iour, , and hyperactivity.54 Con- on October 1, 2021 by guest. Protected copyright. motor. Weakness begins in the proximal mus- version disorder, chronic fatigue syndrome, cles, arms more commonly than legs. Paresis is and somatisation disorder may also be sus- often focal and cranial nerve involvement may pected.70 The occurrence of monthly luteal occur, especially the IIIrd, VIIth, and Xth phase attacks in women, in whom the disorder nerves.38 Clinical progression, which may be seems to be more common,7' may lead to the gradual or stepwise, can continue for up to false diagnosis of premenstrual tension or four weeks after withdrawal of the precipitat- cycloid psychoses being made and the exacer- ing agent and recovery may be protracted. The bation with alcohol may lead to false suspi- pattern of involvement is very variable, may be cions of excessive alcohol intake.32 Pain unilateral ?r bilateral, and may vary from day control may pose particular problems in acute to day. Reflexes are usually diminished, but attacks, and morphine derivatives are often extensor plantars may occur. Guillain-Barre prescribed, and drug dependency has been syndrome65 and are important recorded and may cause considerable manage- differential diagnoses. Sensory involvement, ment problems.72 usually in the form of dysthaesiae, occur in a Santosh and Malhotra73 detailed the pro- third of cases, and may have a bizarre distribu- gression ofpsychiatric symptomatology in a 14 tion,58 which may lead to the suspicion of con- year old Indian patient, who initially devel- version disorder, but is usually rapidly oped an illness characterised by psychomotor followed by more unequivocal neurological retardation, muteness, and fearfulness along signs. Sphincter disturbance is common and with a mild fever and severe abdominal pain. 324 Crimlisk

On subsequent admissions after confirmation to normal. In the subsequent four years she

of acute intermittent porphyria, he presented has continued to have episodes of psychiatric J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.62.4.319 on 1 April 1997. Downloaded from with a variety of symptom clusters including: disturbance, although less often, not all of hypomania with elation, distractibility and which have been associated with a rise in ALA social disinhibition on one occasion; catatonia or PBG. Haematin has not been used. It is with echolalia, posturing and abnormal motor likely that she has an underlying bipolar affec- behaviour on another, and delirium with focal tive disorder unrelated to her porphyria, but neurological signs during a further episode. some attacks may have been made worse or Between attacks his mental state was normal. more refractory in the past by treatment with Thus psychiatric symptoms mimic some psy- porphyrinogenic drugs. chiatric disorders and may vary in the same A 23 year old man had a history of two patient during different episodes. episodes of generalised pain, fever, , vesicular rash, and nausea followed by the development of a paranoid psychosis. These Case reports had resolved over several months but no diag- At the National Hospital for Neurology and nosis had been reached. On admission, he had Neurosurgery, a tertiary referral hospital, only a three week history of abdominal pain, diar- three patients have been diagnosed as having rhoea, fever, headache, delirium, psychosis, porphyria in the past 10 years. These cases and bullous lesions on his legs. On mental cannot be considered representative, but give state examination he had well systematised a flavour of the diagnostic and management persecutory delusions, thought broadcasting, difficulties in patients with neuropsychiatric somatic passivity, and non-verbal auditory hal- symptoms and porphyria. lucinations. Neurological examination dis- A 54 year old woman with longstanding closed mild parkinsonism, increased tone on epilepsy was treated for many years with com- the left side, and bilateral brisk reflexes with binations of phenytoin, phenobarbitone, car- downgoing plantars. He had been treated with bamazepine, and . Over the thioridazine. Other than a mild neutrophilia, preceding 20 years she developed progressive investigations were normal and repeated spot intellectual decline and had episodes of urine PBG and 24 hour ALA, PBG, and por- abdominal symptoms, weight loss, visual hal- phyrins were negative. He was treated initially lucinations, ataxia and muscular weakness with haloperidol and later sulpiride, neither of occurring in association with increased fit fre- which helped, but within five days of being quency. She presented with delirium and vom- changed to chlorpromazine, he began to iting, having been given co-trimoxazole for a improve. A diagnosis of schizophrenia was urinary tract infection. Neurological examina- made. His family continued to seek an alterna- tion disclosed generalised muscle wasting, fin- tive diagnosis and he was later investigated ger-nose ataxia, global weakness, and normal during a further episode in another centre tendon reflexes and a right extensor plantar. abroad. Faecal coproporphyrinogens and 24 Urinary PBG and porphyrins were high (ALA hour urinary coproporphyrinogens were raised was normal) and a diagnosis of acute intermit- and subsequent coproporphyrinogen oxidase tent porphyria was confirmed on enzyme stud- assay confirmed the diagnosis of hereditary ies. After diagnosis and treatment of her coproporphyria. He has had two further seizures with and clonazepam, her episodes, with similar clinical pictures. He has http://jnnp.bmj.com/ mental state and fit frequency improved, but been treated with trifluoperazine as required she died from an episode of and given haematin in the acute phase of his a year later, not apparently related to a further relapses. Episodes have been much more short porphyric attack. lived and between attacks he remains well and A 53 year old woman had a 31 year history functions at a high level, with no negative signs of intermittent psychiatric disturbance charac- of schizophrenia. emotional ideas of These case histories illustrate several of the terised by lability, agitation, on October 1, 2021 by guest. Protected copyright. reference, auditory , and difficulties in the diagnosis and management abdominal pain. The attacks tended to occur of patients with porphyrias. Acute attacks may premenstrually and she required admission up present with life threatening illness and prob- to three times a year. Acute intermittent por- lems may be exacerbated when patients are phyria was diagnosed in a family member and treated with medications which worsen their urinary PBG was measured between attacks. condition. This seems to be a particular prob- This was normal. Several years later, she was lem with seizures, as so many antiepileptic reinvestigated during an attack and the diag- agents are unsuitable when treating fits in por- nosis of acute intermittent porphyria was phyria.74 An acute attack may cause psychi- made on the finding of raised urinary por- atric features indistinguishable from bipolar phyrins. At the time of admission she was affective disorder or schizophrenia, but in our euthymic, with no psychotic or neurological patients, abdominal symptoms-nausea, vom- features, but evidence of mild cognitive under- iting, or weight loss-were present as well. functioning. She was being treated with The clinical outcome is not necessarily good, haloperidol and lithium. Urinary PBG and despite the diagnosis having being made. ALA were raised and enzyme studies con- There are several possible explanations for firmed the previous diagnosis of acute inter- this; for example, patients may still be exposed mittent porphyria. Haloperidol was stopped to porphyrinogenic agents. However, it is and she was started on a high carbohydrate likely that in some patients the porphyria is diet. ALA and PBG concentrations returned modifying the course of an underlying psychi- 325 The little imitator-porphyria: a neuropsychiatric disorder

atric or physical disorder. When there is a of patients in the United Kingdom presented

physical attribution conceivable for psychiatric without a family history and 3% of all patients J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.62.4.319 on 1 April 1997. Downloaded from symptoms, patients as well as physicians and are caused by de novo . An identical psychiatrists often think that the physical dis- has recently been described in 43 of order overrides the psychiatric one. It is 45 South African patients with variegate por- important to recognise that psychiatric symp- phyria, however, it was not present in nine toms should not automatically be put down to British patients with variegate porphyria. This porphyria, as this will tend to deprive patients is thought likely to represent the founder gene of more conventional psychiatric manage- deficit associated with variegate porphyria in ment, both pharmacological and social. South Africa.78 Finally, even when the diagnosis is foremost in the clinicians' minds, it can be missed if appropriate investigations, particularly those Diagnosis using faecal specimens and 24 hour urine sam- Most routine investigations are unhelpful in ples are not undertaken, and repeated if clinical the diagnosis of porphyria. Liver function tests suspicion remains high. and lipids may be abnormal, but not invari- ably. More specialised investigations such as electrophysiology39 or MRI43 showing focal Genetics lesions may be informative, but not diagnostic. Most of the acute porphyrias are inherited in A different approach should be taken to an autosomal dominant manner. Penetrance is diagnosis of the symptomatic patients as low, with as many as 80% of carriers asympto- opposed to that of the asymptomatic relative. matic.4 Occasional coinheritance of two por- The second should be undertaken at a special- phyrias has been described.2675 To date, most ist laboratory. The confirmation that por- genetic characterisation has been undertaken phyria is aetiologically related to a patient's in acute intermittent porphyria. In this disor- symptoms (and not a case of latent porphyria) der, PGB deaminase activity is present at a requires the demonstration of an excess of concentration of about 50% of normal. Two porphyrin precursors, indicating substrate isoenzymes are encoded by a single gene, accumulation at the same time as the occur- which is located on lq.76 One of rence of symptoms. The detailed investigation these isoenzymes is specific to red cells; the of porphyria is complex; thus it is important other is more ubiquitous. Three subtypes of that clinicians have some understanding of the acute intermittent porphyria are recognised. investigative options and pitfalls. Once the One (less than 5% of families) affects only the diagnosis has been made, referral to a specialist ubiquitous isoenzyme. This is important as centre is advisable, for further characterisation assay of the erythroid enzyme is used diagnos- of the disorder, and to offer appropriate fur- tically and a normal assay does not rule out ther investigation of family members. this rare variant. In a further subtype, found in Several different sample types can be used 15% of families, the product of the mutant in the investigation of a patient and these vary allele cross reacts immunologically (CRIM in usefulness depending on which subtype of positive) with antiserum to the normal porphyria is being investigated (table 4). enzyme, but with impaired activity. Only a few Hereditary coproporphyria and variegate por- mutations are found in this subgroup. The phyria are due to enzyme deficits further down http://jnnp.bmj.com/ final type, in which there is no immunological the biosynthetic pathway and the accumulated cross reactivity with the normal enzyme precursors are more fat soluble. These precur- (CRIM negative), is found in 80% of families. sors are preferentially excreted in faeces, This most common group is particularly het- whereas in acute intermittent porphyria, erogeneous, with more than 20 substitutions, abnormalities are predominantly in urine. deletions, and insertions described. Over 100 Porphyrins are very light sensitive and there-

mutations of the PBG deaminase gene have fore samples must be stored in the dark and on October 1, 2021 by guest. Protected copyright. now been identified although all but two occur transported to the laboratory as soon as possi- in only a few families each. A recent analysis ble. The porphyrin concentration in urine is by Whatley et a177 found that about a quarter reduced by 50% in 24 hours under normal

Table 4 Investigations in the neuropsychiatnic porphyrias Unine Faeces Blood ALA PBG URO COPRO COPRO PROTO Enzymes Notes Plumboporphyria High in May be Raised in Raised in 4AIA dehydratase Rare attack raised in attack attack attack Acute intermittent Very high Very high Usually May be May be May be 4PBG deaminase Enzyme may be normal porphyria in attack in attack raised in raised raised raised (normal in a minority) in a minority of patients attack Hereditary Raised in Raised in May be Usually Usually Mildly 4Coproporhyrinogen Urine often normal coproporphyria attack attack raised in raised raised raised oxidase between attacks attack Variegate porphyria Raised in Raised in Usually Usually Mildly Raised lProtoporphyrinogen 75% of attacks are attack attack raised in raised raised oxidase cutaneous only attack ALA = 5-Aminolaevulinic acid; PBG = porphobilinogen; URO = uroporphyrinogen; COPRO = coproporphyrinogen; PROTO = protoporphyrinogen. 326 Crimlisk

lighting.79 Additionally, urinary porphyrin pre- Table 5 When to consider the diagnosis ofporphyria

cursors may only be present in excess for a few Episodic psychiatric disorder in association with: J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.62.4.319 on 1 April 1997. Downloaded from days during the acute attack and therefore Bullous or fragile skin lesions Unexplained recurrent abdominal symptoms samples should be collected as early as possi- A menstrual relation to symptoms ble in the course of the illness. This is less Impaired consciousness or delirium Alcohol induced symptoms likely to be a problem in hereditary copropor- Atypical or variable features phyria or variegate porphyria, when faecal Family history of unexplained death Family history of psychiatric disorder samples remain abnormal for a longer period, In patients with a psychiatric diagnosis of: sometimes permanently. Treatment resistant psychosis Schizoaffective disorder The most common first line screening test Cycloid psychosis used is urine analysis for PBG excretion. A Conversion disorder Somatisation disorder and chronic fatigue syndrome qualitative test is usually first performed (for In the differential diagnosis of the following neurological example, the Watson-Schwartz test), in which disorders: Encephalopathy it is important to include a control to detect Motor neuropathy - for example, Guillain Barre syndrome ingested red dyes from foods or medications.80 Refractory epilepsy Migraine It is often not appreciated that this test has a Early onset significant false positive and false negative Non-anatomical sensory symptoms rate.30 Alternative screening investigations have been suggested,81 but are not yet used universally. If this screening test is positive, samples of urine, faeces, plasma, and serum diagnosis of porphyria should be considered, should all be sent to a specialised laboratory but porphyria may coexist with other physical for more detailed analysis and characterisation and psychiatric disorders. of the type of porphyria.79 The clinician should not be reassured, however, by the finding of a normal urinary PBG in the presence of clinical Management suspicion. More reliable information should TREATMENT OF THE ACUTE ATTACK be sought by repeating spot urine tests, and by Some patients will respond to simple measures analysing 24 hour urine collections and faecal such as increased carbohydrate intake. This is samples (particularly to investigate the possi- most easily achieved with an intravenous glu- bility of the rarer variegate porphyria and cose infusion 2000 kcal carbohydrate per 24 hereditary coproporphyria). The interpreta- hours is recommended. In addition, with- tion of results in variegate porphyria and drawal of precipitants and treatment of inter- hereditary coproporphyria is complex82 and current infection is necessary. Table 2 shows a some workers have advocated the use of bile list of drugs which are thought to be safe and specimens instead of faecal specimens.83 can be used for treatment of intercurrent Several methods are available in specialist problems and relief of symptoms. More severe centres for the further characterisation of the episodes may require considerable supportive porphyrias. High performance liquid chro- treatment, particularly if neuropathy or auto- matography (HPLC) is used to separate out nomic features are present. The use of intra- the differing patterns of excess porphyrins in venous haematin has been advocated for many urine, faeces, and plasma. It is also possible to years, 6 but administration is complicated by assay the relevant enzymes in and its instability in solution and extensive side http://jnnp.bmj.com/ mitochondria. In acute intermittent porphyria, effects (thrombophlebitis and coagulopathy). PBG-D is usually reduced to 50% of normal Recent work by Mustajoki and Nordmann59 but there is overlap with normal subjects,84 using haem arginate has shown a low rate of and in some porphyric families the erythrocyte side effects and favourable response to treat- isoenzyme is normal.89 In variegate porphyria ment in all of 51 attacks ofporphyria studied. A and hereditary coproporphyria the relevant placebo controlled trial86 found a non-signifi- enzymes are more difficult to assay and more cant trend in favour of haem and this arginate on October 1, 2021 by guest. Protected copyright. credence is put on faecal HPLC.79 should now be considered the treatment of choice. It should be started as soon as possible after the onset of an attack, or even prophylac- When to consider porphyria tically and given as four daily courses. A fur- There are three means by which the diagnosis ther treatment option is the use of the of porphyria may be missed. It is rare, and metalloporphyrins such as tin or zinc por- clinicians may be unaware of the wide ranging phyrins. These act as inhibitors of haem oxy- clinical presentation. Diagnostic screening is genase, the enzyme responsible for the most sensitive when investigations are per- breakdown of both endogenous and adminis- formed at the same time as symptoms. This tered haem. There are concerns with regard to means that the diagnosis should be considered the potential toxicity of these metals and their during the early part of the acute admission. use is still experimental .71 Finally, the low sensitivity of some laboratory screening tests means that a normal screening PREVENTION OF ATTACKS test does not exclude the diagnosis. Attempts Patients who have had attacks of porphyria should be made to repeat urine tests and should be advised to avoid potentially por- obtain stool samples if clinical suspicion is phyrinogenic agents, including drugs and alco- high. Liaison with a biochemistry department hol-particularly whisky or red wine.90 with expertise in the porphyrias will be needed Unfortunately, doctors' advice is often to interpret findings. Table 5 shows when the unpalatable. Thunell et a150 found that despite The little imitator-porphyria: a neuropsychiatric disorder 327

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J http://jnnp.bmj.com/ 231-3. attacks of acute porphyria. Q Med 1990;276:355-63. on October 1, 2021 by guest. Protected copyright.