Signs of neuropathy in the lower legs and feet of patients with acute intermittent porphyria

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1 Journal of Internal Medicine 2000; 248: 27±32 Signs of neuropathy in the lower legs and feet of patients with acute intermittent porphyria A. WIKBERG 1,C.ANDERSSON 2 &F.LITHNER 3 From the 1 Department of Advanced Nursing, University of UmeaÊ, 2 Primary Health Care Centre, Arjeplog, and the 3 Department of Medicine, University Hospital, UmeaÊ, Sweden Abstract. Wikberg A, Andersson C, Lithner F (University of UmeaÊ, UmeaÊ; Primary Health Care Centre, Arjeplog; and University Hospital, UmeaÊ, Sweden). Signs of neuropathy in the lower legs and feet of patients with acute intermittent porphyria. J Intern Med 2000; 248: 27±32. Objective. To assess signs of distal neuropathy in patients with acute intermittent porphyria (AIP). Design. A population-based study. Subjects. All patients with DNA-verified AIP $ 18 years of age in the four most northerly counties of Sweden. Intervention. Validated neuropathic signs and tests such as monofilament test, neuropathic pain, dry feet, extensor digitorum brevis (EDB) test, loss of forefoot arch, hammer toes and ulceration. Results. A total of 356 patients were registered and 339 of them (95%) participated in the neuropathy study. The chronic neurological signs were symmetrical and similar to those in type 1 diabetic patients. Significant impairment was found concerning perception, EDB test, lower leg pain, ankle and knee tendon reflexes, but not concerning dry feet, loss of forefoot arch and hammer toes, on comparing patients with manifest versus latent AIP. The neurological signs were more severe in the diabetic patients (n = 298). Five AIP patients had permanent quadriplegia after severe attacks. Conclusions. Patients with manifest AIP had significantly more signs of distal chronic, symmetrical neuropathy of axonal type than did patients with latent AIP. More grave neurological lesions appear to develop after severe attacks. Keywords: acute intermittent porphyria, neuropathy. Introduction The pathogenesis of neurological dysfunction in acute porphyria is not known, but it is suggested that several mechanisms operate either in sequence or in parallel [1]. Measurements of nerve conduction in acute intermittent porphyria (AIP) patients are usually reported to have been performed following attacks and describe axonal degeneration. The pathological changes have been essentially in the peripheral nerves. Both demyelination and axonal degeneration of peripheral nerves and autonomic nerve tissue have been observed [1±4]. The conduction velocity of the nerves is significantly slower in latent AIP patients than in controls, indicating the existence of distal neuropathy also in patients with latent AIP [5]. With a background of knowledge of diabetic neuropathy in the lower legs and feet in several large population-based patient materials [6±9], our aim was to make an identical assessment of signs of neuropathic lesions in the lower legs and feet of patients with AIP. It was considered of clinical and scientific interest to conduct a population-based study in AIP patients in order to estimate the prevalence, nature and severity of distal neuropathy, such as has not, to our knowledge, been reported previously. Patients The material comprised all DNA-verified [10] AIP patients aged $ 18 years in the four most northerly counties of Sweden (n = 386) with a total popula- # 2000 Blackwell Science Ltd 27

2 28 A. WIKBERG et al. tion of 1 million inhabitants. There were 30 (8%) non-participants, none of whom was known to have any neuropathic problems. Seventeen of the patients who were also type 2 diabetics were excluded. Thus, results from 339 AIP patients (Table 1) are presented. The prevalences of distal neuropathy in the manifest and latent AIP groups were compared. Patients were deemed to have latent AIP when they showed laboratory evidence of AIP, despite never experiencing any symptoms, or manifest AIP when they had had at least one attack. Because of the great number of patients scattered over such a large and sparsely populated area (about half of all Sweden), financial and practical constraints obliged us to use simple, easily performed tests in order to be able to examine a large number of patients. All known AIP patients were invited to undergo a standardized investigation including anamnesis (verified by the medical records), physical examination and laboratory tests. The clinical examinations were performed at their local hospitals or health care centres. As it is of interest to compare the severity of the chronic distal neuropathy in the AIP patients with distal neuropathy in other diseases, a historical comparison was performed with a group of type 1 diabetic patients and their matched and healthy control persons [6]. The study of these patients was also population-based; they lived within the same geographical area with a homogenous population, had the same research worker (FL), identical methods were used and the two studies were close in time. Methods The clinical signs used in the present study were performed on both feet and are well known in the extensive literature on diabetic peripheral neuropathy and cover sensory, motor and autonomic neuropathy. Clinical signs The monofilament test for superficial measurements of peripheral sensory neuropathy was defined as insensitivity of the 4.17 monofilament, using standard methods [11]. This validated test [12] replaced the previous tests of perception ± vibration, impaired perception and pain [6±9] ± as it is easier to perform. Neuropathic pain was defined as pain in the limbs despite the absence of a history of trauma or other external cause. `Dry feet' If the patient reported a history of loss of foot perspiration which was confirmed on examination, dry feet were diagnosed [6]. Extensor digitorum brevis (EDB) test Absence of EDB is an early motoric manifestation of distal neuropathy. Dorsiflexion of the toes was used to test the functioning of the EDB muscle. The muscle belly becomes visible and palpable during this manoeuvre [8]. Loss of forefoot arch indicates some loss, a flat forefoot, or a convexity towards the sole of the foot [6]. Hammer toe indicates hyperextension in the metatarsophalangeal joints [6]. Ulceration was defined as a full-thickness, penetrating lesion of the skin [6]. Arterial insufficiency The ankle systolic pressure index (ankle systolic pressure/brachial systolic Table 1 Number and mean age of patients with latent or manifest AIP participating in the peripheral neuropathy study Latent AIP Manifest AIP Women Men Total Women Men Total n (%) 83 (41) 118 (59) 201 (59) 90 (65) 48 (35) 138 (41) Mean years 39 (18±79) 39 (18±79) 39 (18±79) 50 (18±75) 52 (18±80) 51 (18±80)

3 ACUTE INTERMITTENT PORPHYRIA 29 pressure) was calculated and a value of, 0.9 was deemed to indicate arterial insufficiency in the leg [6]. The study was approved by the Medical Ethics Committee, University Hospital, UmeaÊ. Statistics Logistic regression analysis was used to identify significant associations between manifest and latent AIP with distal neuropathy, adjusted for potential confounding variables (age and gender). Results Neuropathic signs in lower legs and feet The results were normalized for age and gender, using a multiple logistic regression model. The neurological signs were symmetrical and similar to those in diabetic patients [6±9], but in contrast to the diabetic patients, none of the AIP patients had foot ulcers or had been subjected to lower leg amputations. There were significant neurological impairments concerning signs of perception, lower leg pain, EDB test, ankle and knee tendon reflexes, but not concerning dry feet, loss of forefoot arch or hammer toes in patients with manifest AIP, when compared with those with latent AIP (Fig. 1). There were no significant differences between men and women with AIP. Two female patients had systolic ankle pressure indexes of 0.8 and 0.8, respectively, and one of the excluded AIP patients with concomitant diabetes had an index of 0.6, but none of these three patients had symptoms. None of the patients had undergone major amputation. This kind of neuropathy was more severe in type 1 diabetic patients when compared with patients with manifest AIP (Table 2). Neuropathy following attacks Five patients (one man and four women) of 138 with manifest AIP (4%) had previously suffered severe recurring attacks over a long period of time and had permanent quadriplegia which always Fig. 1 Odds ratio (OR) of distal neuropathy for patients with manifest (M) acute intermittent porphyria (AIP) versus patients with latent (L) AIP. ORs and 95% confidence intervals are given, adjusted for age and gender, using logistic regression. Number of patients examined (n) and patients with neurological impairments (%) are shown in the lower part of the figure.

4 30 A. WIKBERG et al. Table 2 Prevalence (%) of clinical signs in the lower legs and feet of peripheral neuropathy and arterial insufficiency found at standard examination of patients with latent (L) or manifest (M) acute intermittent porphyria (AIP), type 1 diabetic patients and healthy controls. EDB, extensor digitorum brevis test L-AIP M-AIP Type 1 [6, 8] Control [6, 8] n Age (years, mean) Dry feet Foot ulcers Arterial insufficiency Amputation (leg) Forefoot arch (impaired) Hammer toes EDB (impaired) developed directly in connection with a severe attack. One of them (a woman, 31 years) also had bilateral permanent peroneus pareses. These patients had a predominantly motoric form of neuropathy, with consequent permanent weakness and muscle wasting. Concerning neurological signs, all five patients had no palpable EDB muscle, but sensory and autonomic nerve functions were normal in many of the patients (Table 3). All of them also had renal failure; their creatinine clearances were 39, 24, 25, 43 and 31 ml min m 22, respectively, the reference levels at our hospital laboratory being 65± 130 ml min m 22, women and men alike. One patient (the man) was uraemic and died during the study. These five patients were included in the group of manifest AIP. If they were excluded from this group, odds ratios (ORs) and 95% confidence intervals (CIs) of distal neuropathies for the group of patients with manifest AIP compared with the latent AIP group were not significantly altered, with the exception of the knee tendon reflex with OR = 2.51 and CI (95%) = 0.91±6.90, thus crossing the 1.00 level, indicating a non-significant value. Discussion The present study demonstrates that the chronic, symmetrical type of neuropathy in the patients with manifest AIP is similar to that in diabetic peripheral neuropathy. The behavioural, structural and electrophysiological data in PBGD mice provide convincing evidence that porphyric neuropathy is primarily an axonal motoric form of neuropathy and that the additional changes described are most likely the result of repeated events leading to degeneration and regeneration. This axonal neuropathy occurs despite the absence of acute, reversible symptoms and also in the absense of high levels of delta-aminolaevulinic acid (ALA), suggesting that haem deficiency and Table 3 Prevalence (%) of clinical signs in the lower legs and feet of peripheral neuropathy in five AIP patients with permanent quadriplegia Age Gender Impaired perception, feet Pain in the legs Dry feet Absent ankle reflex Absent knee reflex Impaired extensor dig. brevis Impaired forefoot arch Hammer toes 53 w ± w m w w , neuropathy; 0, no neuropathy; w, women; m, men; ±, missing.

5 ACUTE INTERMITTENT PORPHYRIA 31 consequent dysfunction of haem proteins can cause porphyric neuropathy [13]. This mechanism could also cause the chronic, symmetrical type of neuropathy mentioned above in human beings. A contributory cause could be the fact that, in remission, urinary porphobilinogen excretion is fivefold higher in patients with manifest AIP than in those with latent AIP [10], which could explain why neuropathy is more common in the former than in the latter. The significant differences between patients with manifest versus latent AIP in the present study indicate a chronic, often subclinical, distal neuropathy of axonal type in the lower legs and feet in patients with manifest AIP. Patients with manifest AIP have a more benign neuropathy in their lower legs and feet, when compared with a group of type 1 diabetic patients in previous studies (Table 2), although the diabetic patients were younger. Two reasons for this difference could be that patients with long-term diabetes often have fragile skin on their feet and lower legs [14] and increased atherosclerosis in the arteries of the lower legs [15]. None of the AIP patients had symptoms of distal artery insufficiency, indicating that cutaneous or vascular lesions are of minor importance in patients with AIP, whereas six diabetic patients in the group mentioned above [6] had signs of distal arterial insufficiency and three of them had undergone a major amputation. One explanation could also be that AIP patients have significantly lower cholesterol than do matched control persons [16]. Impaired forefoot arches and hammer toes were found in patients with AIP, but also in the feet of many young and middle-aged healthy control persons [6]. Factors other than neuropathy are therefore of importance and include external pressure from badly fitting shoes. Nerves to the intrinsic muscles of the foot and the muscles themselves are both relatively superficial, and the neurophysiological lesions seen in normal subjects could be due to pressure and the `wear and tear' of daily life [17± 19]. These factors signify that the neuropathic lesions found in some patients with AIP could be due to external factors, but not the difference between latent versus manifest AIP, which is evidence for the existence of peripheral neuropathy in patients with AIP. Information, follow-up examinations and moulded insoles alleviate neuropathic foot deformities in many patients, even in those with pronounced deformities [9]. Quadriplegia in AIP attacks sometimes leaves permanent sequelae. Weakness in arms and legs is a common symptom in severe attacks and could also be an incipient sign of persistent pareses. However, the prevalence of such lesions is small ± only 4% of the patients with manifest AIP in the present study. This type of manifestation directly after severe attacks and mainly affecting motor nerves may be due to a different pathogenesis (vasospasm). The concomitant renal failure in these patients emphasizes the severity of their AIP. Conclusions Patients with manifest AIP exhibit significantly more signs of distal chronic, symmetrical neuropathy of axonal type than patients with latent, mostly subclinical AIP. The chronic, symmetrical neuropathy in patients with manifest AIP seems to be milder than that in young and middle-aged type 1 diabetic patients. In this study, neuropathic lesions in patients with latent AIP did not differ from those in healthy persons. Grave neuropathy affecting mainly motor nerves directly after an attack could be of different pathogenesis. Acknowledgements This work was supported by the county councils of Northern Sweden (Visare Norr), the Ragnar and Torsten SoÈderbergs Foundation and the National Board of Health and Welfare. References 1 UA, Meyer Lindberg RLP, Schuurmans MM.Acute porphyrias: pathogenesis of neurological manifestations. Semin Liver Dis 1998; 18: 43±52. 2 Wochnik-Dyjas D, Niewiadomska M, Kostrzewska E. Porphyric polyneuropathy and its pathogenesis in the light of electrophysiological investigations. J Neurol Sci 1978; 35: 243±56. 3 Becker M, Kramer S. The neurological manifestations of porphyria. A review. Medicine 1977; 56: 411±23. 4 Albers JW, Robertson WC, Daube JR. Electrodiagnostic findings in acute porphyric neuropathy. Muscle Nerve 1978; 1: 292±96. 5 Mustajoki P, SeppaÈlaÈinen AM. Neuropathy in latent

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