Bullous pemphigoid in a leg affected with hemiparesia: a possible relation of neurological diseases with bullous pemphigoid?

ARTICLE

BP is an auto-immune blistering skin disease characterized by the production of antibodies directed against hemidesmosome components of the basement membrane zone. The targeted antigens are two proteins with molecular masses of 230 kD, BP antigen 1 (BPAG1) and 180 kD, BP antigen 2 (BPAG2). Although the cascade of phenomena which leads to blister formation is better known, the pathophysiology of the emergence of these auto-antibodies is less understood. BP is the most frequent auto-immune blistering skin disease and occurs most commonly in elderly, often debilitated patients. Moreover this elderly population has an increased mortality and this fact is perhaps not only explained by their age or by adverse effects due to corticosteroid treatment [1].

A link between BP and neurological disorders needed to be studied. Unilateral BP in hemiplegic patients has been described [2-4]. Association of BP with multiple sclerosis [5-7], amyotrophic lateral sclerosis [8] or Shy-Drager syndrome [9] has been reported.

We report a case of a hemiplegic woman who developed a BP on her hemiparetic side. This observation could be considered as a paradigm of this association. We reviewed the 46 previous cases of BP in the one day-unit of our dermatological department and analyzed from the medical records the presence of neurological disorders and the outcome of these patients. A control group was made from the 46 consecutive oldest patients (older than 71) hospitalized with another skin disease in our one-day-unit. Data were retrospectively studied in the same way.

Methods

The 46 previous consecutive patients with BP hospitalized in our dermatological one-day-unit were studied. The presence of at least 3 of the four following clinical criteria: absence of atrophic scars, absence of head and neck involvement, absence of mucosal involvement and age greater then 70 years and histological and immunohistological (direct immunofluorescence) criteria were used for the diagnosis of BP according to the French Bullous Study Group [13]. A control group was retrospectively made with the 46 consecutive oldest patients (older than 71) hospitalized in our dermatological one-day-unit in 1999-2000. The dermatological diagnosis included melanoma (12), lymphoma (4), Kaposi's sarcoma (3), purpura (3), leg and pressure ulcers (3), pruritus (3), lymphangiosarcoma (2), eczematous dermatitis (2), pemphigus (2), erythroderma (1), other inflammatory skin disorders (2), psoriasis (1), lupus erythematosus (1), scleroderma (1), drug induced eruption (1), mycobacteriosis (1).

Medical records were retrospectively analyzed. Collected data included: age of the patient at the time of the BP diagnosis or at the date of the hospitalization for the control patient, previous reported or concomitant neurological disorders, neurological clinical examination at the time of the diagnosis or at the date of the hospitalization for the control patient, imaging (cerebral IRM or CT scan) when available. Outcome of the BP patients was analyzed in December 1999 on three criteria: dead, alive or lost to follow-up.

Results

A 84-year-old woman was hospitalized for a bullous dermatosis only located on the right side of her body. She had a right hemiparesia and aphasia secondary to ischemic cerebral stroke. Her treatment was nicardipine for arterial hypertension and acetyl salycilate. Examination revealed tense blisters on erythematous plaques localized on the right side of the body (Fig. 1). The mucous membranes were not involved. Clinical diagnosis of BP was confirmed by histological and immunofluorescence data. A skin biopsy specimen revealed a subepidermal blister and direct immunofluorescence showed a linear deposition of C3 and IgG at the dermal epidermal junction. This latter study was positive not only on the right thigh but also on the opposite normal left thigh. Indirect immunofluorescence was negative. A topical treatment with a superpotent local corticosteroid, clobetasol propionate (40 g/day) was quickly effective in healing her skin lesions.

We retrospectively analyzed the medical records of the 46 previous patients with BP in our dermatological one-day-unit. Mean and median age of the patients at the time of the diagnosis was 79 and 85 years, respectively (range 16 to 102 years-old). A neurological disorder was identified in 30 of the 46 patients and included senile dementia /Alzheimer (17/46), cerebral stroke (6/46), epilepsy (2/46), dyskinesia (1/46), trembling (1/46), multiple sclerosis (1/46), lumbar spinal stenosis (1/46), Parkinson's disease (1/46), gonadotropic adenoma with hemiplegia (1/46), peripheral neuropathy (1/46) (Table I). The manifestations of dementia were observed in patient 12 after the beginning of the corticosteroid treatment. Epilepsy resulted in one case from alcohol intoxication and was idiopathic in one case. The 16-year-old patient did not have any evident neurological disease. Only 16 of the 46 patients with BP were without any neurological disease.

In the control group (46 patients average age 82,5; median age 80), only 13 patients had neurological disorders. The diagnosis of these neurological disorders included senile dementia/Alzheimer (2/46), cerebral stroke (3/46), trembling (2/46), Parkinson's disease (1/46), peripheral neuropathy (4/46), psychiatric disorder (1/46). The difference in the prevalence of neurological disorders between the BP patients and the control group was highly statistically significant (p = 0.004).

We separately analyzed the two groups of patients in the patients with BP, N+ (with neurological disorders: 30 patients) and N- (without any neurological disorders: 16 patients). Mean age in N+ and N- groups was 79 years and 75 years, respectively. Nevertheless without the 16-year-old patient that belonged to the N- group the mean age of the N- group was 77 years. The outcome of the patients was studied. At the time of the analysis of the data on the 46 patients (December 1999), 7 were lost (N+: 4, N-: 3), 13 were dead (N+: 10, N-: 3), 26 were alive (N+: 16, N-: 10). The life prognosis also seemed poorer in the N+ group than in the N- group (not statistically significant). It was difficult to study and compare the outcome of the patients of the control group to the BP group because many patients in the control group had malignant disorders (21/46) with poor prognosis and some patients were lost to follow-up.

Discussion

We reported an example of association between BP and a neurological disorder with this patient who developed BP lesions limited to the hemiplegic side. This infrequent association has already been reported [2-4]. It is also possible to relate these cases to localized BP on a stump. Moreover, a link between neurological disorders and BP has been evoked for young patients with multiple sclerosis or amyotrophic lateral sclerosis [5-8]. Recently, observation of an association of Shy-Drager syndrome and bullous pemphigoid [9] provided further evidence of a link between neurological disorders and BP.

We studied the 46 consecutive patients with BP in our one-day-unit. A very high prevalence of neurological disorders was found in our retrospective serie. Our study demonstrated a higher prevalence of neurological diseases in BP patients as compared to the control group. This control group seems representative of BP patients because (a) it was made with consecutive patients who were hospitalized in the same dermatological one-day-unit, (b) they were only selected by being older than 71 years, (c) the average age of these patients was higher than that of the BP patients (d) the data were retrospectively collected in the same way from the medical records.

Interestingly, the life prognosis seemed poorer in the patients who had neurological disorders and may also explain the poor prognosis observed in these patients even when topical corticosteroids replace systemic corticosteroids.

Thus, this study suggests that there is a possible high prevalence of neurological disorders in patients with BP. But, a prospective case control study with neurological examination and psychometrical evaluation is necessary to confirm these data. We speculate that neuroautoimmunity associated with the aging process or neurological disorder may be involved in pemphigoid development via autoimmune response against dystonin, which shares homology with BPAg1. Recently a gene dystonin (dt) coding for a neuronal isoform of the BPAg1 was identified as being responsible for dystonia musculorum in a mouse model [10]. Dystonia musculorum is a hereditary sensory neuropathy and results from inactivation of the two dt alleles [16]. Dt is a cytoplasmic protein that is present in different compartments of a mature neuron (dendrites, axon, cell body) [17]. In the dystonia musculorum mouse, neurodegeneration is observed in the ganglia and neurons, and is associated with an accumulation of neurofilaments [18]. Dt shares homology with BPAg1 in the C terminal region. Interestingly, epitopes recognized by antibodies in BP directed to BPAg1 are located in this homologous region (Fig. 2) [19]. It was demonstrated that the immune response against BPAg1 is also directed against dystonin. Antibodies against BPAg1 (10C5 mAb) raised against an epitope in the central portion of the human BPAg1 protein recognized dt on mouse brain section and spinal cord [12]. We suggest that BP may be a marker of neuroimmune response and also of a neurodegeneration.

Such an association between bullous dermatosis and proteins which participate in the organization of cellular cytoskeleton or extracellular matrix is not limited to bullous pemphigoid. Association of epidermolysis bullosa and muscular dystrophy was recently demonstrated for plectin. It is possible that the strong homology between plectin, which is present in the desmosomal plaque, and dystrophin is responsible for this association [19].

Article accepted on 25/1/01

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