Chronic Inflammatory Demyelinating Polyradiculoneuropathy and Graves' Disease in an Adolescent with Crohn's Disease

Inflammatory bowel disease appears to result from complex interactions among susceptibility genes, the environment and the immune system ⁽¹⁾. Numerous case reports have described an association between inflammatory bowel disease, particularly ulcerative colitis, and other immune-mediated diseases. In large epidemiologic studies from Europe, 7% to 9% of patients with ulcerative colitis had an associated autoimmune disorder compared with 2% of a control group ^(2,3). This higher prevalence was not found in patients with Crohn's disease ⁽²⁾. Hyperthyroidism is one of these associated disorders. Another immune-mediated chronic disease, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) has been associated with both ulcerative colitis and Crohn's disease in a few case reports ^(4-9).

In the following, we report a pediatric patient with a diagnosis of CIDP, Crohn's disease, and Graves' disease. To our knowledge, this is the first report of clustering of these three immune-mediated conditions.

CASE REPORT

A 14-year-old boy was brought to the Children's Hospital of New Orleans with muscle weakness, numbness, diarrhea, and weight loss. He had a 5-month history of two to three liquid stools per day associated with abdominal cramps and a weight loss of 15 lb. Recently, he had noted some blood in his stools. Over the past 2 months, he noted weakness of his hands and feet progressing to the point that he was unable to hold a glass with one hand. He also had proximal leg weakness and was able to walk only with support. Numbness and paraesthesias developed in his right thumb and subsequently in other digits. He had experienced occasional swallowing difficulties, double vision, and a migraine-type headache for 5 weeks. There was no exposure to toxic agents, drugs, or alcohol. His family history was negative for gastrointestinal, endocrine, neurologic, or autoimmune diseases. His medical history was unremarkable except for asthma, with no attacks in recent years.

On physical examination, he looked thin and ill. His weight was 54.8 kg (40th percentile for age) and his height was 178.5 cm (90th percentile for age). Examination of his neck, chest, and abdomen produced normal findings, and his mental status was intact. Findings in a complete eye examination were also normal. Neurologic examination revealed right sixth nerve palsy, bilateral seventh nerve palsy, reduced distal muscle strength, decreased sensation to pinprick and light touch in both hands, and absent tendon reflexes. He was unable to walk on his toes but had no signs of ataxia. Babinski sign was negative bilaterally. He had no clinical signs of hyperthyroidism. Anal inspection revealed no perianal lesions.

Laboratory investigations showed microcytic anemia (hemoglobin 9.1 g/dl), decreased serum albumin (3.0 mg/dl), increased γ-globulin, a borderline antinuclear antibody titer of 1:80 (normal, < 1:80), and a decreased complement component C4 of 11 (normal, >20). The following laboratory test results were normal: platelet count, sedimentation rate, C-reactive protein, C-3, serum creatine phosphate kinase and aldolase, vitamin B₁₂, and folate in serum. In addition, antibodies to double-stranded DNA, SSA, SSB, SM, and cardiolipin were negative. A spinal tap revealed normal cerebrospinal fluid. Stool examinations for bacterial pathogens, Clostridium difficile toxin, and ova and parasites were negative. A chest radiograph, an electrocardiogram, and an echocardiogram were normal. Immunologic work-up revealed no evidence for cellular or humoral immune deficiency. HLA haplotypes were A2, -; B45, 50(w6); Cw6, w7; DR1, 13(52); DQ1,7. Class II HLA oligotypes were DRB1-0102/1304; DRB3-0202; DQB1-01/0301.

Results of thyroid function tests were as follows: T4, 13.2 µg/dl (normal, <13 µg/dl); T3, 311 ng/ml (normal, <230 ng/ml); antithyroid peroxidase antibody, 82 IU/ml (normal, <30); TSH, <0.1 µIU/ml (normal, >0.5 µIU/ml); TSH-receptor antibody, 43 TBII (normal, <15); antithyroid globulin antibody <40 IU/ml (normal, <120 IU/ml). On the basis of these findings, a diagnosis of subclinical autoimmune hyperthyroidism was made. Serum antibodies against a prototypic strain of a human intracisternal A-type retroviral particle type 1 were detected by a sensitive and specific immunoblotting assay ⁽¹⁰⁾.

A colonoscopy revealed an edematous and erythematous mucosa with loss of vascularity and focal areas of friability without ulcers. There were areas of preserved vascularity in the right colon and rectum. The descending and sigmoid colon were most affected. Analysis of colonic biopsy specimens revealed dense chronic inflammatory infiltrates extending to the submucosa with occasional crypt abscesses and cryptitis, microscopic fissures reaching through the muscularis mucosa with reepithelialization, regenerative epithelium with goblet cell depletion, giant cells, and occasional granulomas. Findings in an esophagogastroduodenoscopy were normal, but a duodenal specimen showed focal acute and chronic inflammation with gland destruction and a giant cell. A barium upper gastrointestinal and small bowel follow-through examination produced normal results. The findings were compatible with Crohn's disease of the colon and duodenum.

Peripheral nerve conduction studies revealed decreased conduction velocities and low amplitudes for both sensory and motor nerves, suggestive of a primary demyelinating neuropathy with secondary axonal injury. A sural nerve biopsy specimen showed a mononuclear inflammatory infiltrate surrounding the perineurial and endoneurial blood vessels (Fig. 1), without evidence of demyelination, remyelination or significant loss of nerve fibers. On the basis of these electrophysiologic and histologic findings, the diagnosis of CIDP was made.

Fig. 1

Before the diagnosis of Crohn's disease was established, the patient was treated with a 10-day course of intravenous immunoglobulin (400 mg/kg·day) with no improvement of the neuropathy. Subsequently, the diagnosis of Crohn's disease was established, and treatment with 60 mg/day prednisone, 1 g sulfasalazine twice daily, and folic acid resulted in complete remission of the Crohn's disease and gradual improvement of neurologic symptoms. Thyroid function tests also normalized and electrophysiologic studies 2 months into the treatment course showed improvement. Seven months later, the patient showed clinical signs of hyperthyroidism including palpitations, nervousness, heat intolerance, diaphoresis, frequent urination, and dry skin. Mild proptosis and a mild soft and uniform thyromegaly were noted. There was no significant weight loss, and vital signs were normal. Levels of T-4, T-3 and TSH-receptor antibodies were again elevated. A ¹²³I thyroid scan showed a diffusely enlarged gland with increased tracer activity consistent with Graves' disease.

Propylthiouracil (100 mg three times a day) was prescribed. Three months later, the symptoms of hyperthyroidism had disappeared, and thyroid function test results normalized. The prednisone dose was changed to an every-other-day schedule, gradually tapered, and maintained at 20 mg every other day. At 16 years of age, 2 years after his initial symptoms, the patient had a relapse of neuropathy with numbness in his feet and hands, mild generalized weakness in his arms, and decreased sensation in his distal lower extremities. Repeat nerve conduction studies showed lower amplitudes and slower conduction velocities than before, with multifocal conduction block and temporal dispersion. Electromyography showed no acute denervative activity but a markedly decreased recruitment of rapidly firing, polyphasic, high-amplitude motor unit potentials in hand intrinsics. On the basis of these findings, prednisone was increased to 60 mg per day, and 1 mg/kg·day azathioprine was begun and gradually increased to 2.8 mg/kg·day to achieve improvement of neurologic symptoms. The Crohn's disease remained in remission, and thyroid function test results remained normal.

At 17 years of age, the patient had a 3-day course of plasmapheresis for worsening of neurologic symptoms. Some improvement of muscle strength was noted. He also reported intermittent swelling and pain in his knees, which required treatment with prednisone. On a follow-up visit at 18 years of age, he was relatively asymptomatic and was working part time. His medication included 200 mg/day azathioprine, 50 mg prednisone every other day on a tapering schedule, 100 mg propylthiouracil three times daily, and 2 g sulfasalazine daily. To date, he has had no gastrointestinal symptoms since his first episode of Crohn's disease 4 years ago.

He has two younger siblings (one 13-year-old girl and one 10-year-old boy), who are described as healthy. Their thyroid function test results, antinuclear antibody, and human insulin antibodies were normal. The sister had a mildly elevated TSH receptor antibody titer of 16 (normal, <10). This titer was not elevated in the brother (9.6).

DISCUSSION

Extraintestinal disorders in patients with inflammatory bowel disease may occur concurrently with intestinal disease activity or follow an independent course ⁽³⁾. Our patient was unusual in that he had Crohn's disease simultaneously occurring with two conditions, CIDP and Grave's disease, that are believed to have autoimmune mechanisms. The clinical course of these three diseases is of particular interest: CIDP brought the patient to seek medical attention, was most debilitating and difficult to control, required unusually high doses of immune suppression, and had a relapsing course. In contrast, Crohn's disease remained in remission over the entire observation period of 4 years. Grave's disease was initially subclinical, but became symptomatic and required specific therapy 9 months after the initial presentation at a time when the Crohn's disease was in full remission. The discrepant courses suggest that these three immune-mediated diseases are separate entities occurring in one person with a genetic susceptibility for all three conditions. CIDP is rarely associated with inflammatory bowel disease. We found seven case reports of peripheral neuropathy compatible with the diagnosis of CIDP in adult patients with inflammatory bowel disease, two with ulcerative colitis, and five with Crohn's disease ^(4-9). In the pediatric age group, only cases of peripheral neuropathy related to folate deficiency or metronidazole treatment were reported ^(11,12). Our patient did not receive metronidazole, and his plasma levels of vitamin B₁₂ and folate were normal. In addition, his sural nerve biopsy specimen showed perivascular lymphocytic infiltrates suggestive of an immune-mediated inflammatory process.

Hyperthyroidism has been associated with ulcerative colitis in epidemiologic studies ^(2,3,13) and case reports ^(14-17). However, there is no increased prevalence of hyperthyroidism in patients with Crohn's disease ⁽²⁾, and no case reports on this association are available. The primary autoantigen in Graves' disease is the TSH-receptor, and the presence of antibodies to this receptor as well as of antithyroid peroxidase antibodies indicates thyroid autoimmunity.

Recently, evidence for a retroviral trigger of Graves' disease has accumulated. Jaspan et al. ⁽¹⁰⁾ found an incidence of 88% of serum antibodies against a prototypic strain of a human intracisternal A-type retroviral particle type I in Graves' disease patients. This incidence was less than 2% in normal controls and less than 15% in other autoimmune diseases. These antibodies were also present in our patient. Our patient did not exhibit class II HLA haplotypes previously linked to Graves' disease ⁽¹⁸⁾. However, the fact that his sister has circulating TSH-receptor antibodies may indicate a genetic susceptibility in the family. It remains to be established whether the genetically susceptible person's exposure to retroviral antigens precipitates the autoimmune responses leading to Graves' disease or other immune-mediated diseases.

Acknowledgment: The authors thank Jonathan B. Jaspan (deceased) from the Department of Medicine, Tulane University Medical Center, for measuring antibodies against a human retroviral particle.