Israel Medical Association Journal

Background: Transthyretin (TTR)-associated familial amyloid polyneuropathy (FAP) is an autosomal dominant multisystem disease with neurological and extra-neurological manifestations. It is caused by various mutations in the TTR gene leading to the formation of insoluble amyloid.

Objectives: To describe the clinical and genetic findings in patients with TTR-associated FAP in Israel.

Methods: We evaluated eight patients clinically and genetically during the years 2006 to 2011.

Results: At onset, all the patients exhibited sensory loss of the lower and upper limbs, five patients experienced muscle pain, and one patient had lower limb weakness. Five patients had autonomic nervous system manifestations, and four demonstrated evidence of amyloid cardiomyopathy. Nerve conduction studies showed sensorimotor axonal neuropathy in all patients. Sural nerve biopsies were obtained in five patients; only three biopsies revealed amyloid deposit. In four patients of Yemenite descent, genetic analysis of the TTR gene demonstrated ser77tyr mutation. One patient of Tunisian descent and one Ashkenazi patient harbored the val30met mutation. One patient of Iranian descent showed val32ala mutation, and another Ashkenazi patient showed phe33leu mutation.

Conclusions: TTR-associated FAP is a progressive and fatal disease that exists in the Israeli population and is unproportionally common among Yemenite Jews. This disease may be under-diagnosed and should be considered in the differential diagnosis of any patient with rapidly progressive neuropathy, especially with autonomic involvement or extra-neural features. The absence of amyloid in nerve biopsy should not rule out the diagnosis.  
 

The DRESS syndrome (drug reaction with eosinophilia and systemic symptoms), also known as DIHS (drug-induced hypersensitivity syndrome), presents clinically as an extensive mucocutaneous rash, accompanied by fever, lymphadenopathy, hepatitis, hematologic abnormalities with eosinophilia and atypical lymphocytes, and may involve other organs with eosinophilic infiltration, producing damage in several systems, especially kidney, heart, lungs, and pancreas. The pathogenesis is related to specific drugs (especially the aromatic anticonvulsants), altered immune response, sequential reactivation of herpes virus, and association with some HLA alleles. Glucocorticoids are the basis for the treatment of the syndrome, which may be given with intravenous immunoglobulin and, in selected cases, ganciclovir. This article reviews current concepts regarding the interaction of drugs, viruses and immune responses during this complex adverse-drug reaction.
 

Background: Common peroneal neuropathies, usually located at the fibular head, are one of the causes of drop foot, a condition often evaluated in the electromyography laboratory.

Objectives: To study the motor conduction properties of the common peroneal nerve and its branches of distribution in patients with paralyzed drop foot, several weeks after their first stroke, assuming that its inversion position can cause neuropathy around the fibular neck.

Methods: We performed peroneal nerve conduction study on 76 legs of 38 patients, 12–73 days after their first stroke. All the patients had flaccid drop foot on the involved side. The stimulating electrode was placed at the postero-lateral aspect of the fibular neck. Motor nerve conduction latency and compound muscle action potential amplitude were measured along the proximal part of the deep and the superficial peroneal nerve, comparing the paralyzed to the sound leg. Paired sample t-test and paired t-test were used to compare the nerve conduction properties between the sound and the paralytic leg. The linear liaison between the two legs was determined by Pearson coefficient and the test based on it.

Results: The differences between motor conduction latencies and between CMAP[1] amplitudes, comparing the paralyzed to the sound side, recorded in both the deep peroneal nerve and the superficial peroneal nerve, were statistically significant (P < 0.05).
Conclusions: It seems that the permanent equino-varus position of the paralyzed foot might affect common peroneal nerve conduction properties at the level of the fibular neck by demyelination, axonopathy, or both. Possible reasons for these pathological changes are nerve traction or nerve compression, but temperature changes in the paralytic leg should also be considered. Ankle-foot orthoses can be prescribed for prevention or correction of deformities of the foot and ankle and reduction of the weight-bearing forces

Objectives: To describe an alternative de-loading method using a fiberglass removable walking cast.

Methods: This prospective uncontrolled study comprised 24 diabetic and non-diabetic patients with a single planter neuropathic ulcer. Exclusion criteria included the presence of osteomyelitis or cellulites, peripheral vascular disease, severe foot or leg edema, more than one ulcer on the treated foot, ulcers on the other foot, visual problems, gait instability, and personality or psychiatric problems. All patients were treated with the removable fiberglass de-loading cast. At each weekly follow-up visit the cast was removed. Data were collected using a clinical report form.

Results: The ulcer healed completely in 21 of the 24 patients treated (87.5%). The mean time for healing was 6.8 weeks (range 3–20 weeks, SD = 4.2). New ulcers developed in six patients (25% of the group).

Conclusions: The effectiveness and safety of the method is comparable to that of the total contact cast, but is less labor intensive because the cast is manufactured only once and serves for the whole length of treatment. Improving the technique is expected to lower the complication rate.

Background: Transcobalamin II is a serum transport protein for vitamin B₁₂. Small variations in TC-II[1] affinity were recently linked to a high homocysteine level and increased frequency of neural tube defects. Complete absence of TC-II or total functional abnormality causes tissue vitamin B₁₂ deficiency resulting in a severe disease with megaloblastic anemia and immunologic and intestinal abnormalities in the first months of life. This condition was described in hereditary autosomal-recessive form. Low serum TC-II without any symptoms or clinical significance was noted in relatives of affected homozygotes.

Objectives: To study 23 members of a four-generation family with hereditary vitamin B₁₂ deficiency and neurologic disorders.

Methods: Thorough neurologic, hematologic and family studies were supplemented by transcobalamin studies in 20 family members.

Results: Partial TC-II deficiency was found in 19 subjects. Apo TC- II (free TC-II unbound to vitamin B₁₂) and total unsaturated B₁₂ binding capacity were low in all tested individuals but one, and holo TC-II (TC-II bound by vitamin B₁₂) was low in all family members. The presentation of the disease was chronic rather than acute. Early signs in children and young adults were dyslexia, decreased IQ, vertigo, plantar clonus and personality disorders. Interestingly, affected children and young adults had normal or slightly decreased serum vitamin B₁₂ levels but were not anemic. Low serum B₁₂ levels were measured in early adulthood. In mid-late adulthood megaloblastic anemia and subacute combined degeneration of the spinal cord were diagnosed. Treatment with B₁₂ injections resulted in a significant improvement. The pedigree is compatible with an autosomal-dominant transmission. This family study suggests a genetic heterogeneity of TC-II deficiency.

Conclusions: We report the first family with a hereditary transmitted condition of low serum TC-II (partial TC-II deficiency) associated with neurologic and mental manifestations in childhood. Partial TC-II deficiency may decrease the amount of stored cobalamin, resulting in increased susceptibility to impaired intestinal delivery of cobalamin and predisposing to clinically expressed megaloblastic anemia at a later age. Partial TC-II deficiency should be suspected in families with megaloblastic anemia and in individuals with neurologic and mental disturbances – despite normal serum vitamin B₁₂ levels. Low serum UBBC[2] and apo TC-II should confirm the diagnosis. Early vitamin B₁₂ therapy may prevent irreversible neurologic damage.

Paraneoplastic syndromes are disorders associated with cancer but without a direct effect of the tumor mass or its metastases on the nervous system. Small cell carcinoma of lung associated with paraneoplastic sensory neuronopathy and/or paraneoplastic encephalomyelitis with the presence of anti-Hu antibodies has been termed “anti-Hu syndrome. Anti-­Hu associated PSN-PEM is an immune disorder in which both cell-mediated and humoral mechanisms are involved. Patients are consiaered affected by Anti-Hu associated PSN-PEM when they develop clinical signs and symptoms of CNS dysfunction and/or sensory neuropathy not caused by metas­tases or other disorders, and serum or cerebrospinal fluid is positive for Hu abs. SCLC is found in more than 90% of patients with cancer and positive Hu abs. Individual patients with Hu abs associated to SCLC may suffer PSN-PEM, Iimbic encephalitis, brainstem encephalopathy, opsoclonus-myoclo­nus, paraneoplastic cerebellar degeneration or myelopathy. Hu abs have a specificity of 99% and sensitivity of 82% in detecting paraneoplastic neurological syndromes. There are two types of treatment: the first is to treat the cancer, the second is to suppress the immune reaction with the use of corticosteroids, cyclophosphamide, azathioprine, plasma ex­change, intravenous immunoglobulin and immunoadsorption however, treatment of paraneoplastic syndromes is generally unsatisfactory.