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

REVIEW

The little imitator-porphyria: a neuropsychiatricdisorder

Helen L Crimlisk

Department ofNeuropsychiatry,Institute ofNeurology,Queen Square,London, UKH L CrimnliskAddress for correspondence:Dr Helen L Crimlisk,Neuropsychiatry Group,Department of ClinicalNeurology, Institute ofNeurology, Queen Square,London WC1N 3BG.Received 25 June 1996and in final revised form18 December 1996Accepted 8 January 1997

AbstractThree common subtypes of porphyriagive rise to neuropsychiatric disorders;acute intermittent porphyria, variegateporphyria, and coproporphyria. The sec-ond two also give rise to cutaneous symp-toms. Neurological or psychiatricsymptoms occur in most acute attacks,and may mimc many other disorders.The diagnosis may be missed because it isnot even considered or because of techni-cal problems, such as sample collectionand storage, and interpretation of results.A negative screening test does not excludethe diagnosis. Porphyria may be overrep-resented in psychiatric populations, butthe lack of control groups makes thisuncertain. The management of patientswith porphyria and psychiatric symptomscauses considerable problems. Threecases are described to illustrate some ofthese issues. Advances in molecular biol-ogy permit identification of patients andlatent carriers in the family. Care to avoidrelapses and improved treatments havereduced the mortality.

(3 Neurol Neurosurg Psychiatry 1997;62:319-328)

Keywords: porphyria; psychosis; metalloporphyrins

Porphyria is derived from the Greek word por-phuros meaning purple. Protoporphyrin IX isthe biologically active substance, an importantfeature of which is its metal binding capacity.Both chlorophyll and haem are metallopor-phyrins and are involved in the processes ofenergy capture and utilisation in animals andplants. The description of the porphyrins byNobel laureate Hans Fischer' in 1930 as:

"The compounds which make grass greenand blood red."

indicates the central position of these sub-stances in the biological sciences.The porphyrias are a heterogeneous group

of overproduction diseases, resulting fromgenetically determined, partial deficiencies inhaem biosynthetic enzymes. Their manifesta-tions are broad and their relevance in neu-ropsychiatric disorders may sometimes beoverlooked.2 Indeed, porphyria was describedby Waldenstr6m3 as the "the little imitator,"by contrast with syphilis, "the big imitator" ofthe early 20th century. Terminology is confus-ing and they have been categorised in severaldifferent ways: as acute, non-acute, hepatic,cutaneous, and neurovisceral, among others.The most useful clinical categorisation isbased on symptoms (table 1), and divides thedisease into cutaneous, neuropsychiatric, andmixed disorders.

Table 1 Biochemistry of the porphyrias (neuropsychiatric involvement in bold)Pathway Enzyme Disorder Inheritance Neuropsychiatric CutaneousGlycine + succinyl-CoA

* ALA synthetase5-aminolaevulinic acid (ALA)

* ALA dehydratase Plumboporphyria Autosomal + + + 0recessivePorphobilinogen (PBG)

* PBG deaminase Acute intermittent porphyria Autosomal + ++ 0dominantHydroxymethylbilane

* Uroporphyrinogen synthetase Congenital erythropoietic Autosomal 0 + + +porphyria recessiveUroporphyrinogen m (URO)

* Uroporphyrinogen oxidase Porphyria cutanea tarda Autosomal 0 + + +dominant (20%)or acquiredCoproporphyrinogen m (COPRO)

* Coproporphyrinogen oxidase Hereditary coproporphyria Autosomal + + + +dominantProtoporphyrinogen IX (PROTO)

* Protoporphyrinogen oxidase Variegate porphyria Autosomal + + + + +dominantProtoporphyrin IX

* Ferrochelatase Erythropoietic protoporphyria Autosomal 0 + + +haem dominant

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Most porphyrins are inborn errors ofmetabolism, but some-for example, por-phyria cutanea tarda-may be acquired. Theneuropsychiatric porphyrias (for example,acute intermittent porphyria) and the mixedporphyrias (for example, variegate porphyriaand hereditary coproporphyria) may give riseto acute, potentially fatal, neurovisceral crises,with neuropathy, delirium, psychosis, auto-nomic instability, and abdominal pain.Variegate porphyria and hereditary copropor-phyria also cause dermatological features, usu-ally in the form of a bullous or erythematousrash. Plumboporphyria has only beendescribed in a few cases but resembles acuteintermittent porphyria clinically. Other condi-tions such as hereditary tyrosinaemia and leadpoisoning may produce secondary abnormali-ties of porphyrin metabolism with similar clin-ical and biochemical features.

Eighty per cent of patients who have inher-ited haem biosynthetic enzyme deficienciesnever develop symptomatic disease and arethought to be "latent porphyrics".4 Relativelylittle progress has been made in predictingwho will develop clinical features,5 althoughwomen seem to be at much greater risk thanmen. The characterisation of individual molec-ular defects in the genes encoding the haembiosynthetic enzymes has led to the identifica-tion of homozygous forms-for example,harderoporphyria, the homozygous form ofcoproporphyria.6 These are often associatedwith more florid clinical features.

Recent developments in molecular geneticsmake the accurate diagnosis of porphyria pos-sible in the proband as well as allowing geneticcounselling and screening in family members.Appropriate advice on avoiding potentiallyporphyrinogenic drugs has been shown toreduce the incidence of attacks.7 The preva-lence of the phenotype may be increasing,7making detection of apparently latent carriersmore important. Whereas advances have beenmade in the diagnostic tests available, pitfallsin diagnosis are still common8 resulting in thefalse belief that "porphyria has beenexcluded". Finally, a recent family study9found a higher incidence of generalised anxi-ety disorder in "latent" relatives of patientswith acute intermittent porphyria, raisingdoubts as to the relation between phenotypeand genotype in so-called "latent" carriers.

Historical aspectsThe first description of acute porphyria as aclinical syndrome was in 1889 by Stokvis.'°The attack occurred after the administrationof sulphonal, a drug which had been intro-duced as a hypnotic a year earlier. Congenitalerythropoietic porphyria was recognised as aninborn error of metabolism by Garrod in1923.1" Important work on the description ofthe clinical condition originated in areas wherethe incidence of porphyria was high-forexample, acute intermittent porphyria inSweden'2 and variegate porphyria in CapeTown.'3 14 Porphyria has become topical in theUnited Kingdom in the past few decades as a

result of the hypothesis of McAlpine andHunter'5 that George III's frequent bouts ofinsanity were due to porphyria, although thisview is still controversial.'6 17 Porphyria hasalso been implicated in van Gogh's illness'8and in the obstetric history of Queen Anne.'9Waldenstrom in Sweden20 and Dean in

South Africa'" have commented on the rarityof manifest porphyria before the introductionof porphyrinogenic drugs such as barbituratesand sulphonamides. In South Africa, wherethe 20 original Free Burghers have multiplied12 500 fold since the 17th century, this auto-somal dominant condition did not confer lifethreatening disadvantages on people with thegenotype. The widespread use of potentiallyporphyrinogenic drugs and greater alcoholconsumption may have led to increased clini-cal manifestation of the underlying geneticdefect.7

EpidemiologyThe estimated gene frequency of acute inter-mittent porphyria is 1-2 in 10 00020; however,there is great regional variability. The preva-lence of variegate porphyria among theAfrikaans population of South Africa, wherethe introduction of the disorder has beentraced back to a Dutch immigrant in 1688,'3 is1 in 250. The resultant high awareness of var-iegate porphyria may have resulted in anunderestimate of the importance of acuteintermittent porphyria.'6 Other than in SouthAfrica, acute intermittent porphyria seems tobe the most common, with ratios of acuteintermittent porphyria:variegate porphyria:hereditary coproporphyria of 100:15:7 inGermany2' and 100:50:26 in Czechoslovakia.22In addition to the three autosomal dominantsubtypes of porphyria mentioned above,plumboporphyria, an autosomal recessive con-dition which presents with neuropsychiatricsymptoms, has been described in six casesworldwide23 and a localised cluster of cases,known as "Dobson's complaint" (a combina-tion of the enzyme deficits responsible foracute intermittent porphyria and variegateporphyria with a similar clinical picture) hasbeen described in Cheshire, UK.24 An out-break of "secondary porphyria" occurred inTurkey after the exposure of 4000 people to afungicide, hexachorobenzene, resulting in amixed porphyric picture in many people aswell as the death of many infants throughbreast milk transmission.25 Porphyria is lesscommon before adolescence and after themenopause, and symptomatic cases are fourtimes more common in women, with a particu-lar preponderance premenstrually.26

Waldenstrbm'2 first showed the presence ofexcess porphyrin metabolites in asymptomaticrelatives of patients with acute intermittentporphyria and proposed the now acceptedhypothesis of autosomal dominance with vari-able penetrance. Mustajoki and Koskelo27measured porphobilinogen deaminase (PGB-D) activity in healthy Finnish blood donors inan attempt to calculate the prevalence of thegenotype in the population. They found

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321The litde imitator-porphyria: a neuropsychiatric disorder

unequivocally low values in 0A4% and border-line concentrations in a further 0-4%, suggest-ing a high rate of latent carriers. Thus thefrequency of the responsible genes in the popu-lation is high and more than 80% of those whoinherit the genetic defect do not developsymptoms.4The prevalence of porphyria in psychiatric

populations was first investigated by Kaelblinget al,28 who found that 35 of 2500 psychiatricpatients admitted to a short term intensivecare psychiatric unit had a positive screeningWatson-Schwarz reaction. Twelve of thesewere considered to have manifest acute inter-mittent porphyria on clinical grounds (pointprevalence 0 48%). A similar study inAustralia,29 using quantitative PBG analysisalone, found a prevalence of 0O16%. Theresults of these earlier studies can be criticisedbecause of the use of a single test, which isnow known to have a high rate of false positiveand false negative results.30 Tishler et alscreened nearly 4000 psychiatric inpatientsand calculated a point prevalence of 0-21%. Inthis study, screening was based initially on theWatson-Schwartz reaction, with 24 hour urineanalysis of 5-aminolaevulinic acid (ALA) andporphobilinogen (PBG) in those with a posi-tive result. Of the 70 who screened positive,eight were thought to have manifest acuteintermittent porphyria on the basis of furthertests, including assay of the enzyme PBGdeaminase. In a further 10 positive patients,acute intermittent porphyria was thought notto be aetiologically related to their symptoms,despite abnormal enzyme concentrations,because of the absence of raised urinary por-

phyrin precursors. Most of the patientsdescribed in these studies had diagnoses ofschizophrenia, schizoaffective disorder, or

atypical psychoses.These estimates seem to represent an

increased prevalence of both latent and mani-fest porphyria in psychiatric populations.However, there are significant methodologicalproblems with the studies to date; in particu-lar, given the wide geographical variability, theabsence of control groups. It remains unclearwhether porphyria was causally related to thepsychiatric disorder seen. An alternative expla-nation is that porphyria modifies an alreadypresent psychiatric disorder in a way whichmakes patients more likely to be admitted tohospital, such as by worsening symptoms or

inducing apparent "drug resistant" or refrac-tory cases. Equally, no systematic follow up

studies have been performed on the effect ofremoving porphyrinogenic agents from suchpatients' medication regimens, although case

reports suggest that early improvements may

occur.31 32

BiochemistryThe haem biosynthetic pathway is tightly con-

trolled by several mechanisms allowing rapidadjustment when demand for haem, the endproduct, changes. The first enzyme in thepathway, ALA synthase, is an important partof this regulation and seems to be tissue spe-

cific, with different genes encoding both liverand erythroid isoenzymes. Thus the hepaticisoenzyme of ALA is inducible when demandfor haem rises but the erythroid isoenzyme isproduced to subserve the more constantdemand for haemoglobin synthesis. Hepatichaem biosynthesis is under negative feedbackthrough the activity ofALA synthase. Enzymeturnover is high, which permits rapid adjust-ment.33 Feedback can be mediated at thestages of transcription and transport into mito-chondria, as well as by post-translational activ-ity of the enzyme itself. The system isexquisitely sensitive to rapid oscillations inhaem demand.23

In the porphyrias, a partial enzyme defi-ciency leads to overproduction of precursorssuch as ALA and PBG, which may induce theclinical picture by acting as false neurotrans-mitters. Alternatively, the clinical picture maybe caused by haem deficiency.34 The recentdevelopment of a mouse model for acute inter-mittent porphyria35 should help to resolve thisissue. Table 1 shows the biosynthetic pathwayfor haem with the porphyria subtypes causedby enzyme deficiency along this pathway.Secondary porphyria results in a similar bio-chemical and clinical picture to the mixed por-phyrias. The exclusion of toxins-for example,alcohol, lead or hexachlorobenzene-as acause is important. Hereditary tyrosinaemiatype 1, due to a partial deficiency of theenzyme fumaryl acetoacetate hydrolyase,results in a secondary deficit of ALA dehy-dratase, causing a similar clinical and bio-chemical picture to plumboporphyria.'6 Leadinhibits ALA dehydratase, as well as severalother enzymes in the haem biosynthetic path-way and may produce both an acute crisis aswell as a chronic neuropathy with intellectualdecline and other mental changes.37

PathogenesisBoth neurological and gastrointestinal symp-toms are thought to result from neuronal dys-function. Histological findings in peripheraland autonomic nerves include oedema, irregu-larity of the myelin sheaths, thinned andirregular axons, axonal vacuolisation, anddegeneration and cellular infiltration.'8Electrophysiology shows muscle denervationand decreased motor nerve conduction veloci-ties.'9 The pathogenesis of the cerebral mani-festations, however, remains unclear. Themain hypotheses are metabolic abnormalities,ischaemia, demyelination, and oxidative stress.Pathology of the CNS includes vacuolisationof neurons, focal perivascular demyelination,and reactive glial proliferation.40 Unfor-tunately, postmortem pathological findingsbear little relation to the clinical features inlife, supporting the theory that many of theclinical features may be caused by profoundmetabolic abnormalities.One hypothesis is that ALA may disturb

neurophysiological mechanisms through itsstructural similarity to y-aminobutyric acid(GABA).41 Others have proposed that multifo-cal ischaemia is responsible, through vaso-

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spasm. Black et al42 showed reversible angio-graphic changes, indicating arterial vasospasmin porphyric encephalopathy. King andBragdon43 described the MRI findings in a 20year old woman with an acute, drug inducedattack of acute intermittent porphyria charac-terised by abdominal pain, nausea, visual hal-lucinations, lethargy, and seizures. On theeighth day MRI showed multiple high signalintensity lesions, predominantly in frontal andparietal lobes. When she was asymptomatic 10days after treatment, the lesions had resolved.Thunell et al44 proposed that oxidative stresswas important in the clinical manifestationsand free radical formation may contribute tothe sometimes irreversible pathologicalchanges.40 Complement activation and media-tors of inflammation have also been impli-cated.45 In variegate porphyria and hereditarycoproporphyria, free radicals produced by theabsorption of solar energy result in erythemaor bullous lesions.23 Skin histology is charac-terised by homogeneous PAS positive thicken-ing and IgG deposition in vessel walls.

Precipitating agentsA partial deficiency in one of the enzymes ofhaem biosynthesis is not usually sufficient toresult in the clinical syndrome. Many peoplewith the genetic abnormality never developsymptoms, despite exposure to high doses ofporphyrinogenic agents, and it is likely thatthere are other factors which modify theresponse of the body. Most of the agentswhich predispose to the clinical picture of por-phyria deplete intracellular haem, which isthought to be due to increased production ofthe haemoprotein cytochrome P-450. Thismay be caused by induction of the cytochromeP-450 enzyme system, depletion of free haemdue to direct inhibition of its synthesis, ordirect degradation of haem.46Many patients presenting with acute attacks

have ingested a known porphyrinogenic drugwhich could account for the attack.47 A com-mittee has been set up to compile a databaseon the porphyrinogenicity of drugs.48 The cur-rent list of drugs thought to be porphyrino-genic is long and details can be found in theBritish National Formulary49 or obtained fromthe Porphyria Research Group in Cardiff(Porphyria Research Unit, Department ofMedical Biochemistry, Heath Park, CardiffCF4 4XN, UK). Common culprits includeantibiotics such as sulphonamides and, ery-

Table 2 Drugs probably safe in porphyria

Symptoms Safe treatment options

Pain Narcotics-for example, codeine, morphineParacetamol, aspirin

Hypertension/tachycardia PropranololAnxiety/sleeplessness Propranolol, lorazepam, chloral hydrateNausea/vomiting Chlorpromazine, promazine, cyclizineDelirium/psychosis Phenothiazines-for example, chlorpromazine,

trifluoperazine, droperidolSeizures Lorazepam, paraldehyde, bromides,

GabapentinDepression LofepramineInfection Penicillins, aminoglycosidesConstipation Lactulose, neostigmine

thromycin, sedatives such as barbiturates, ben-zodiazepines and sulpiride, hormone productssuch as the oral contraceptives, anabolicsteroids, hormone replacement therapy andtamoxifen, antiepileptics such as phenytoinand carbamazepine, drugs of abuse includingcocaine and amphetamines, as well as manycommonly prescribed drugs such as antihista-mines, diuretics, baclofen, metoclopramide,many of the tricyclic antidepressants, anddiclofenac. Table 2 shows a list of drugs whichare generally thought to be safe and can beused in the treatment of an acute porphyricattack.

Alcohol has long been noted to precipitateacute attacks of porphyria in some patients.Ethanol, although a good inducer of thecytochrome P-450 system in vitro, it is a lesspotent inducer in intact rats.50 In humans,there is wide variability in alcohol toleranceamong porphyric patients.5' The evidence thatalcohol itself is porphyrinogenic is conflicting.Thunell et a150 failed to show a relationbetween the amount of alcohol consumed, orthe frequency of ingestion and the develop-ment of porphyric symptoms in acute inter-mittent porphyria. The intake of somealcoholic beverages, especially red wine andwhisky, was significantly related to symptoms.They proposed that long chain alcohols andpolyphenolic compounds such as tannins wereresponsible for inducing porphyric attacksrather than ethanol itself.

Starvation may induce the activity ofhepatic ALA synthase, an effect which is over-come by the administration of glucose. Thusdieting and eating disorders may precipitate anacute attack. The mechanism of this effect isuncertain, but calorie restriction has beenshown to be associated with a significant risein urinary excretion of ALA and PBG, whichis reversed by increased carbohydrate intake.52Glucose may inhibit ALA synthase.23Oestrogen and progesterone aggravate por-phyria52 and cyclic attacks most commonlyoccur in the luteal phase. The relationbetween cigarette smoking and recurrentattacks may be due to metabolic induction ofhaem.53 The claim that stress, surgery, andinfection are precipitants has not been sup-ported by published data. Acute porphyria waspreviously thought to be rare before adoles-cence, possibly because children are less likelyto be exposed to precipitants such as drugs oralcohol. There are recent reports of acuteattacks in children, often related to the use ofpotentially porphyrinogenic medication.54-56

Clinical manifestationsThe clinical manifestations of the porphyriasare variable and the potential for misdiagnosisis great (table 3).125759

In patients with recognised acute attacks,the premorbid personality and mental healthof patients between attacks seems normal.60The clinical course may be chronic or acute onchronic,6' and episodes may be self limiting orprogressive. The variability of the clinicalcourse as well as the episodic nature and

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The little imitator-porphyria: a neuropsychiatric disorder

Table 3 Signs and symptoms in acute porphyria (most data refer to acute intermittentporphyria)

Percentage of cases

Stein and Mustajoki andWaldenstrom Goldberg Tschudy Nordmann195712 1959¶7 197058 199359

Signs and symptoms n = 321 n = 50 n = 46 n =51

Abdominal pain 85 94 95 96Mental symptoms 55 58 40 19Constipation 48 84 48 78Pain elsewhere - 52 50 25Vomiting 59 88 43 84Muscle weakness 42 68 60 8Hypertension 40 54 36 57Tachycardia 28 64 80 79Fever 37 14 9 -

Respiratory paralysis 14 10 9 -

Convulsions 10 16 20 1Sensory loss 9 38 26 -

bizarre features mean that porphyria may goundiagnosed and be put down to somatisation,conversion disorder, or to other psychiatricdisorders. Several authors have describedpatients long incarcerated in mental hospitalswho are eventually diagnosed with por-phyria,586162 although there are no reports onthe outcome of these patients.Of the 29 attacks in 25 patients analysed by

Ridley,38 10 patients died. Sudden death sug-gesting cardiac arrythmias was the most com-mon cause of death. Later studies have shownlower mortality rates. Kauppinen andMustajoki,63 analysing their series of 206patients, found that both the mortality associ-ated with attacks and the risk of further attackshas greatly reduced over time, commensuratewith better recognition, improved treatmentregimens, and counselling of patients to pre-vent risk taking behaviour. Their group hasalso confirmed findings by Hardell64 showingan increased incidence of hepatocellular carci-noma (which accounted for 8-3% of deaths intheir porphyric patients) and chronic renalfailure (which accounted for 4% of deaths). Inpatients who survive a severe acute attack,complete recovery is the rule, although recoverymay be protracted. Distal weakness and sen-sory loss are the most persistent features.

Physical symptoms and signsThe neuropathy in porphyria is primarilymotor. Weakness begins in the proximal mus-cles, arms more commonly than legs. Paresis isoften focal and cranial nerve involvement mayoccur, especially the IIIrd, VIIth, and Xthnerves.38 Clinical progression, which may begradual or stepwise, can continue for up tofour weeks after withdrawal of the precipitat-ing agent and recovery may be protracted. Thepattern of involvement is very variable, may beunilateral ?r bilateral, and may vary from dayto day. Reflexes are usually diminished, butextensor plantars may occur. Guillain-Barresyndrome65 and lead poisoning are importantdifferential diagnoses. Sensory involvement,usually in the form of dysthaesiae, occur in athird of cases, and may have a bizarre distribu-tion,58 which may lead to the suspicion of con-version disorder, but is usually rapidlyfollowed by more unequivocal neurologicalsigns. Sphincter disturbance is common and

seizures occur in nearly a quarter of cases.Autonomical neuropathy is responsible formany of the systemic features of acute por-phyria including abdominal pain, vomiting,constipation, hypertension, and tachycardia.Abnormal autonomic cardiac reflexes havebeen shown to occur during an attack, butregress on remission66 and abnormal gastroin-testinal mobility has also been found.67Seizures may be focal or generalised and mayrarely be the presenting feature of porphyria.68A recent epidemiological survey found thatseizures are less common than previouslythought, with a lifetime prevalence of 5 1%among patients with manifest acute intermit-tent porphyria and 2-2% of all those with thegenotype.69 In the United Kingdom, 75% ofcases of variegate porphyria have skin lesionsalone, the remainder dividing equally betweenmixed and neuropsychiatric alone. In heredi-tary coproporphyria, skin lesions alone areuncommon. Cutaneous features in variegateporphyria and hereditary coproporphyria com-prise photosensitivity, skin fragility, bullouslesions, facial hypertrichosis, and hyperpig-mentation in addition to the neuropsychiatricfeatures, which are otherwise indistinguishablefrom those of acute intermittent porphyria.

Psychiatric symptomsMost of the larger case series have been under-taken by neurologists or physicians, thus"mental symptoms" are not fully characterisedand their incidence is likely to have beenunderestimated. Anxiety, restlessness, insom-nia, and depression and psychosis occur oftenand may be persisting features.23 Detailed psy-chiatric assessment has been limited to smallseries or case reports. In one family, acuteattacks of acute intermittent porphyria pre-sented as aggressive, impulsive behaviour withdepressed mood and suicidal attempts.32Others have described schizophrenic symp-toms such as social withdrawal, auditory hallu-cinations, persecutory delusions, andcatatonia31; affective symptoms with emotionallability, insomnia and grandiose delusions;and conduct disorder with disruptive behav-iour, encopresis, and hyperactivity.54 Con-version disorder, chronic fatigue syndrome,and somatisation disorder may also be sus-pected.70 The occurrence of monthly lutealphase attacks in women, in whom the disorderseems to be more common,7' may lead to thefalse diagnosis of premenstrual tension orcycloid psychoses being made and the exacer-bation with alcohol may lead to false suspi-cions of excessive alcohol intake.32 Paincontrol may pose particular problems in acuteattacks, and morphine derivatives are oftenprescribed, and drug dependency has beenrecorded and may cause considerable manage-ment problems.72

Santosh and Malhotra73 detailed the pro-gression of psychiatric symptomatology in a 14year old Indian patient, who initially devel-oped an illness characterised by psychomotorretardation, muteness, and fearfulness alongwith a mild fever and severe abdominal pain.

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On subsequent admissions after confirmationof acute intermittent porphyria, he presentedwith a variety of symptom clusters including:hypomania with elation, distractibility andsocial disinhibition on one occasion; catatoniawith echolalia, posturing and abnormal motorbehaviour on another, and delirium with focalneurological signs during a further episode.Between attacks his mental state was normal.Thus psychiatric symptoms mimic some psy-chiatric disorders and may vary in the samepatient during different episodes.

Case reportsAt the National Hospital for Neurology andNeurosurgery, a tertiary referral hospital, onlythree patients have been diagnosed as havingporphyria in the past 10 years. These casescannot be considered representative, but givea flavour of the diagnostic and managementdifficulties in patients with neuropsychiatricsymptoms and porphyria.A 54 year old woman with longstanding

epilepsy was treated for many years with com-binations of phenytoin, phenobarbitone, car-bamazepine, and primidone. Over thepreceding 20 years she developed progressiveintellectual decline and had episodes ofabdominal symptoms, weight loss, visual hal-lucinations, ataxia and muscular weaknessoccurring in association with increased fit fre-quency. She presented with delirium and vom-iting, having been given co-trimoxazole for aurinary tract infection. Neurological examina-tion disclosed generalised muscle wasting, fin-ger-nose ataxia, global weakness, and normaltendon reflexes and a right extensor plantar.Urinary PBG and porphyrins were high (ALAwas normal) and a diagnosis of acute intermit-tent porphyria was confirmed on enzyme stud-ies. After diagnosis and treatment of herseizures with valproate and clonazepam, hermental state and fit frequency improved, butshe died from an episode of status epilepticusa year later, not apparently related to a furtherporphyric attack.A 53 year old woman had a 31 year history

of intermittent psychiatric disturbance charac-terised by emotional lability, agitation, ideas ofreference, auditory hallucinations, andabdominal pain. The attacks tended to occurpremenstrually and she required admission upto three times a year. Acute intermittent por-phyria was diagnosed in a family member andurinary PBG was measured between attacks.This was normal. Several years later, she wasreinvestigated during an attack and the diag-nosis of acute intermittent porphyria wasmade on the finding of raised urinary por-phyrins. At the time of admission she waseuthymic, with no psychotic or neurologicalfeatures, but evidence of mild cognitive under-functioning. She was being treated withhaloperidol and lithium. Urinary PBG andALA were raised and enzyme studies con-firmed the previous diagnosis of acute inter-mittent porphyria. Haloperidol was stoppedand she was started on a high carbohydratediet. ALA and PBG concentrations returned

to normal. In the subsequent four years shehas continued to have episodes of psychiatricdisturbance, although less often, not all ofwhich have been associated with a rise in ALAor PBG. Haematin has not been used. It islikely that she has an underlying bipolar affec-tive disorder unrelated to her porphyria, butsome attacks may have been made worse ormore refractory in the past by treatment withporphyrinogenic drugs.A 23 year old man had a history of two

episodes of generalised pain, fever, confusion,vesicular rash, and nausea followed by thedevelopment of a paranoid psychosis. Thesehad resolved over several months but no diag-nosis had been reached. On admission, he hada three week history of abdominal pain, diar-rhoea, fever, headache, delirium, psychosis,and bullous lesions on his legs. On mentalstate examination he had well systematisedpersecutory delusions, thought broadcasting,somatic passivity, and non-verbal auditory hal-lucinations. Neurological examination dis-closed mild parkinsonism, increased tone onthe left side, and bilateral brisk reflexes withdowngoing plantars. He had been treated withthioridazine. Other than a mild neutrophilia,investigations were normal and repeated spoturine PBG and 24 hour ALA, PBG, and por-phyrins were negative. He was treated initiallywith haloperidol and later sulpiride, neither ofwhich helped, but within five days of beingchanged to chlorpromazine, he began toimprove. A diagnosis of schizophrenia wasmade. His family continued to seek an alterna-tive diagnosis and he was later investigatedduring a further episode in another centreabroad. Faecal coproporphyrinogens and 24hour urinary coproporphyrinogens were raisedand subsequent coproporphyrinogen oxidaseassay confirmed the diagnosis of hereditarycoproporphyria. He has had two furtherepisodes, with similar clinical pictures. He hasbeen treated with trifluoperazine as requiredand given haematin in the acute phase of hisrelapses. Episodes have been much more shortlived and between attacks he remains well andfunctions at a high level, with no negative signsof schizophrenia.

These case histories illustrate several of thedifficulties in the diagnosis and managementof patients with porphyrias. Acute attacks maypresent with life threatening illness and prob-lems may be exacerbated when patients aretreated with medications which worsen theircondition. This seems to be a particular prob-lem with seizures, as so many antiepilepticagents are unsuitable when treating fits in por-phyria.74 An acute attack may cause psychi-atric features indistinguishable from bipolaraffective disorder or schizophrenia, but in ourpatients, abdominal symptoms-nausea, vom-iting, or weight loss-were present as well.The clinical outcome is not necessarily good,despite the diagnosis having being made.There are several possible explanations forthis; for example, patients may still be exposedto porphyrinogenic agents. However, it islikely that in some patients the porphyria ismodifying the course of an underlying psychi-

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325The little imitator-porphyria: a neuropsychiatric disorder

atric or physical disorder. When there is a

physical attribution conceivable for psychiatricsymptoms, patients as well as physicians andpsychiatrists often think that the physical dis-order overrides the psychiatric one. It isimportant to recognise that psychiatric symp-

toms should not automatically be put down to

porphyria, as this will tend to deprive patientsof more conventional psychiatric manage-

ment, both pharmacological and social.Finally, even when the diagnosis is foremost inthe clinicians' minds, it can be missed ifappropriate investigations, particularly thoseusing faecal specimens and 24 hour urine sam-

ples are not undertaken, and repeated if clinicalsuspicion remains high.

GeneticsMost of the acute porphyrias are inherited inan autosomal dominant manner. Penetrance islow, with as many as 80% of carriers asympto-matic.4 Occasional coinheritance of two por-

phyrias has been described.2675 To date, mostgenetic characterisation has been undertakenin acute intermittent porphyria. In this disor-der, PGB deaminase activity is present at a

concentration of about 50% of normal. Twoisoenzymes are encoded by a single gene,

which is located on chromosome 1 lq.76 One ofthese isoenzymes is specific to red cells; theother is more ubiquitous. Three subtypes ofacute intermittent porphyria are recognised.One (less than 5% of families) affects only theubiquitous isoenzyme. This is important as

assay of the erythroid enzyme is used diagnos-tically and a normal assay does not rule outthis rare variant. In a further subtype, found in15% of families, the product of the mutantallele cross reacts immunologically (CRIMpositive) with antiserum to the normalenzyme, but with impaired activity. Only a fewmutations are found in this subgroup. Thefinal type, in which there is no immunologicalcross reactivity with the normal enzyme

(CRIM negative), is found in 80% of families.This most common group is particularly het-erogeneous, with more than 20 substitutions,deletions, and insertions described. Over 100mutations of the PBG deaminase gene havenow been identified although all but two occur

in only a few families each. A recent analysisby Whatley et a177 found that about a quarter

of patients in the United Kingdom presentedwithout a family history and 3% of all patientsare caused by de novo mutations. An identicalmutation has recently been described in 43 of45 South African patients with variegate por-

phyria, however, it was not present in nineBritish patients with variegate porphyria. Thisis thought likely to represent the founder gene

deficit associated with variegate porphyria inSouth Africa.78

DiagnosisMost routine investigations are unhelpful inthe diagnosis of porphyria. Liver function testsand lipids may be abnormal, but not invari-ably. More specialised investigations such as

electrophysiology39 or MRI43 showing focallesions may be informative, but not diagnostic.A different approach should be taken to

diagnosis of the symptomatic patients as

opposed to that of the asymptomatic relative.The second should be undertaken at a special-ist laboratory. The confirmation that por-

phyria is aetiologically related to a patient'ssymptoms (and not a case of latent porphyria)requires the demonstration of an excess ofporphyrin precursors, indicating substrateaccumulation at the same time as the occur-

rence of symptoms. The detailed investigationof porphyria is complex; thus it is importantthat clinicians have some understanding of theinvestigative options and pitfalls. Once thediagnosis has been made, referral to a specialistcentre is advisable, for further characterisationof the disorder, and to offer appropriate fur-ther investigation of family members.

Several different sample types can be usedin the investigation of a patient and these vary

in usefulness depending on which subtype ofporphyria is being investigated (table 4).Hereditary coproporphyria and variegate por-phyria are due to enzyme deficits further downthe biosynthetic pathway and the accumulatedprecursors are more fat soluble. These precur-

sors are preferentially excreted in faeces,whereas in acute intermittent porphyria,abnormalities are predominantly in urine.Porphyrins are very light sensitive and there-fore samples must be stored in the dark andtransported to the laboratory as soon as possi-ble. The porphyrin concentration in urine isreduced 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 Rareattack raised in attack attack

attackAcute intermittent Very high Very high Usually May be May be May be 4PBG deaminase Enzyme may be normalporphyria in attack in attack raised in raised raised raised (normal in a minority) in a minority of patients

attackHereditary Raised in Raised in May be Usually Usually Mildly 4Coproporhyrinogen Urine often normalcoproporphyria attack attack raised in raised raised raised oxidase between attacks

attackVariegate porphyria Raised in Raised in Usually Usually Mildly Raised lProtoporphyrinogen 75% of attacks are

attack attack raised in raised raised oxidase cutaneous onlyattack

ALA = 5-Aminolaevulinic acid; PBG = porphobilinogen; URO = uroporphyrinogen; COPRO = coproporphyrinogen; PROTO = protoporphyrinogen.

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lighting.79 Additionally, urinary porphyrin pre-

cursors may only be present in excess for a fewdays during the acute attack and thereforesamples should be collected as early as possi-ble in the course of the illness. This is lesslikely to be a problem in hereditary copropor-

phyria or variegate porphyria, when faecalsamples remain abnormal for a longer period,sometimes permanently.The most common first line screening test

used is urine analysis for PBG excretion. Aqualitative test is usually first performed (forexample, the Watson-Schwartz test), in whichit is important to include a control to detectingested red dyes from foods or medications.80It is often not appreciated that this test has a

significant false positive and false negativerate.30 Alternative screening investigationshave been suggested,81 but are not yet useduniversally. If this screening test is positive,samples of urine, faeces, plasma, and serum

should all be sent to a specialised laboratoryfor more detailed analysis and characterisationof the type of porphyria.79 The clinician shouldnot be reassured, however, by the finding of a

normal urinary PBG in the presence of clinicalsuspicion. More reliable information shouldbe sought by repeating spot urine tests, and byanalysing 24 hour urine collections and faecalsamples (particularly to investigate the possi-bility of the rarer variegate porphyria andhereditary coproporphyria). The interpreta-tion of results in variegate porphyria andhereditary coproporphyria is complex82 andsome workers have advocated the use of bilespecimens instead of faecal specimens.83

Several methods are available in specialistcentres for the further characterisation of theporphyrias. High performance liquid chro-matography (HPLC) is used to separate outthe differing patterns of excess porphyrins inurine, faeces, and plasma. It is also possible toassay the relevant enzymes in cytoplasm andmitochondria. In acute intermittent porphyria,PBG-D is usually reduced to 50% of normalbut there is overlap with normal subjects,84and in some porphyric families the erythrocyteisoenzyme is normal.89 In variegate porphyriaand hereditary coproporphyria the relevantenzymes are more difficult to assay and more

credence is put on faecal HPLC.79

When to consider porphyriaThere are three means by which the diagnosisof porphyria may be missed. It is rare, andclinicians may be unaware of the wide rangingclinical presentation. Diagnostic screening ismost sensitive when investigations are per-formed at the same time as symptoms. Thismeans that the diagnosis should be consideredduring the early part of the acute admission.Finally, the low sensitivity of some laboratoryscreening tests means that a normal screening

test does not exclude the diagnosis. Attemptsshould be made to repeat urine tests andobtain stool samples if clinical suspicion ishigh. Liaison with a biochemistry departmentwith expertise in the porphyrias will be neededto interpret findings. Table 5 shows when the

Table 5 When to consider the diagnosis ofporphyria

Episodic psychiatric disorder in association with:Bullous or fragile skin lesionsUnexplained recurrent abdominal symptomsA menstrual relation to symptomsImpaired consciousness or deliriumAlcohol induced symptomsAtypical or variable featuresFamily history of unexplained deathFamily history of psychiatric disorder

In patients with a psychiatric diagnosis of:Treatment resistant psychosisSchizoaffective disorderCycloid psychosisConversion disorderSomatisation disorder and chronic fatigue syndrome

In the differential diagnosis of the following neurologicaldisorders:

EncephalopathyMotor neuropathy - for example, Guillain Barre syndromeRefractory epilepsyMigraineEarly onset dementiaNon-anatomical sensory symptoms

diagnosis of porphyria should be considered,but porphyria may coexist with other physicaland psychiatric disorders.

ManagementTREATMENT OF THE ACUTE ATTACKSome patients will respond to simple measuressuch as increased carbohydrate intake. This ismost easily achieved with an intravenous glu-cose infusion 2000 kcal carbohydrate per 24hours is recommended. In addition, with-drawal of precipitants and treatment of inter-current infection is necessary. Table 2 shows alist of drugs which are thought to be safe andcan be used for treatment of intercurrentproblems and relief of symptoms. More severeepisodes may require considerable supportivetreatment, particularly if neuropathy or auto-nomic features are present. The use of intra-venous haematin has been advocated for manyyears, 6 but administration is complicated byits instability in solution and extensive sideeffects (thrombophlebitis and coagulopathy).Recent work by Mustajoki and Nordmann59using haem arginate has shown a low rate ofside effects and favourable response to treat-ment in all of 51 attacks of porphyria studied. Aplacebo controlled trial86 found a non-signifi-cant trend in favour of haem arginate and thisshould now be considered the treatment ofchoice. It should be started as soon as possibleafter the onset of an attack, or even prophylac-tically and given as four daily courses. A fur-ther treatment option is the use of themetalloporphyrins such as tin or zinc por-phyrins. These act as inhibitors of haem oxy-genase, the enzyme responsible for thebreakdown of both endogenous and adminis-tered haem. There are concerns with regard tothe potential toxicity of these metals and theiruse is still experimental .71

PREVENTION OF ATTACKSPatients who have had attacks of porphyriashould be advised to avoid potentially por-phyrinogenic agents, including drugs and alco-hol-particularly whisky or red wine.90Unfortunately, doctors' advice is oftenunpalatable. Thunell et a150 found that despite

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The little imitator-porphyria: a neuropsychiatric disorder

counselling at centres of excellence, 87% ofpatients with inducible porphyria continued todrink alcohol, despite reporting that it resultedin clinical exacerbation of the disease. Patientsshould also be warned about the importanceof maintaining a high carbohydrate diet and ofthe potential danger of intercurrent infectionsand dieting and emotional stressors. In womenwith attacks related to menstruation, suppress-ing ovulation with the luteinising hormonereleasing hormone (LHRH) analogue,Buserelin, has been shown to reduce the num-ber of attacks.87 When exposure to a precipi-tant has taken place, haematin can be initiatedprophylactically if the consequences are likelyto be severe.

Identification of carriersThe identification of carriers in the familyshould be undertaken wherever possible. Bothpatients and carriers should be given advice onthe likely precipitants of porphyria. In addi-tion, carriers as well as patients should wearmed-alert bracelets in case of the necessity foremergency treatment. It is currently unknownwhat proportion of asymptomatic carriers goon to develop symptoms and acute attacks canbe fatal; therefore, advice should be given toall. Patient and carer support groups havebeen set up in conjunction with some centresand this has proved beneficial, particularly inthe light of recent publicity about porphyria,which has resulted in patients fearing incipientmadness.

ConclusionThe porphyrias are rare but important disor-ders. Their recognition is increasingly impor-tant in view of the widespread use ofpotentially porphyrinogenic agents. Whetherporphyria is of relevance in chronic psychiatricillness remains controversial. No studies todate have satisfactorily considered the issue of acontrol population. The highly variable natureof neurological and psychiatric symptoms inacute porphyria adds to the difficulty in mak-ing a diagnosis. The potential for iatrogenicattacks in both unsuspected and diagnosedpatients should be recognised. Treatment mayworsen or prolong both psychiatric and neuro-logical symptoms. There are particular prob-lems associated with treating patients withcoexistent porphyria and psychiatric disorder.

There is still widespread misunderstandingamong clinicians with regard to the interpreta-tion of laboratory results and the techniquescurrently used have unacceptably high falsepositive and false negative rates.

Finally, it is important that patients arediagnosed and family members screened toavoid unnecessary exposure to potentially dan-gerous drugs, thereby reducing morbidity andmortality from this disorder.7I thank Professors Maria Ron, George Elder, and TimothyPeters for their encouragement and help, and an anonymousreviewer for his comments.

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