Pathology of early- vs late-onset TTR Met30 familial amyloid polyneuropathy.

BACKGROUND: Late-onset type I familial amyloid polyneuropathy (FAP TTR Met30) cases unrelated to endemic foci in Japan show clinical features setting them apart from early-onset cases in endemic foci. OBJECTIVE: To compare pathologic features between the early- and late-onset types. METHODS: Pathologic findings in FAP TTR Met30 with onset before age 50 in relation to endemic foci (11 cases) were compared with those in 11 later-onset cases unrelated to endemic foci. RESULTS: Sural nerve biopsy specimens showed predominantly small-fiber loss in early-onset cases; variable fiber size distribution, axonal sprouting, and relatively preserved unmyelinated fibers characterized late-onset cases. Autopsy cases representing both groups showed amyloid deposition throughout the length of nerves and in sympathetic and sensory ganglia, but amounts were greater in early-onset cases. Amyloid deposition and neuronal cell loss were greater in sympathetic than dorsal root ganglia in early-onset cases; the opposite was true in late-onset cases. Size assessment of remaining neurons in these ganglia suggested predominant loss of small neurons in early-onset cases but loss of neurons of all sizes in late-onset cases. Transthyretin-positive, Congo red-negative amorphous material was more conspicuous in nerves from late- than early-onset cases. In extraneural sites, amyloid was more conspicuous in thyroid and kidney from early-onset cases and in heart and hypophysis from late-onset cases. In early-onset cases, cardiac amyloid deposition was prominent in the atrium and subendocardium but was conspicuous throughout the myocardium in late-onset cases. CONCLUSION: The pathology of early- and late-onset FAP TTR Met30 correlated well with differences in clinical findings.

Chronic inflammatory demyelinating polyneuropathy presenting with features of GBS.

The authors report five patients with inflammatory demyelinating polyneuropathy with a Guillain-Barré syndrome (GBS)-like onset and initial clinical features, but with persistent symptoms similar to chronic inflammatory demyelinating polyneuropathy (CIDP). Patients in the chronic phase improved with corticosteroid or IV immunoglobulin therapy. Patients with apparent GBS who show persistent symptoms may benefit from corticosteroids or other treatment that is beneficial in the management of CIDP.

ABO-incompatible auxiliary partial orthotopic liver transplant for late-onset familial amyloid polyneuropathy.

A 60-year-old Japanese man with late-onset familial amyloid polyneuropathy type I (FAP transthyretin Met30) showed clinical improvement following auxiliary partial orthotopic liver transplantation (APOLT) from an ABO-incompatible living related donor. Preoperatively, plasmapheresis and immunosuppressant drugs were used to reduce serum antibodies against the donor's ABO type. APOLT was chosen so the residual liver could sustain the patient in the event of hyperacute rejection. OLT is applicable to late-onset FAP transthyretin Met30, and APOLT can be considered in ABO-incompatible cases.

Spinal cord magnetic resonance imaging demonstrates sensory neuronal involvement and clinical severity in neuronopathy associated with Sjögren's syndrome.

OBJECTIVES: To determine spinal cord MRI findings in neuronopathy associated with Sjögren's syndrome and their correlation with severity of sensory impairment. METHODS: Clinical and electrophysiological features, pathological findings in the sural nerve, and hyperintensity on T2* weighted MRI in the spinal dorsal columns were evaluated in 14 patients with neuronopathy associated with Sjögren's syndrome. RESULTS: Of 14 patients, 12 showed high intensity by T2* weighted MRI in the posterior columns of the cervical cord. High intensity areas were seen in both the fasciculus cuneatus and gracilis in nine patients, who showed severe and widespread sensory deficits in the limbs and trunk; these patients also had a high frequency of autonomic symptoms. Somatosensory evoked potentials often could not be elicited. Hyperintensity restricted to the fasciculus gracilis was seen in three patients, who showed sensory deficits restricted to lower limbs without trunk involvement, or with only partial limb involvement; no autonomic symptoms were noted. The two patients who did not show high intensity areas in the dorsal columns showed restricted sensory involvement in the limbs. All patients showed axonal loss predominantly affecting large fibres, without axonal sprouting. CONCLUSIONS: High intensity areas on T2* weighted MRI in the spinal dorsal columns reflect the degree of sensory neuronal involvement in neuronopathy associated with Sjögren's syndrome; this finding could also be a helpful marker for estimating severity of this neuronopathy.

Postgastrectomy polyneuropathy with thiamine deficiency.

OBJECTIVE: Polyneuropathy has been reported after gastrectomy performed to treat various lesions. Although thiamine deficiency is a possible cause of this neuropathy, the pathogenesis still remains to be clarified. Seventeen patients with peripheral neuropathy with thiamine deficiency after gastrectomy are described. METHODS: Seventeen patients with polyneuropathy after gastrectomy accompanied by thiamine deficiency were selected. Patients were restricted to those with total or subtotal gastric resection to treat ulcer or neoplasm. Patients who had undergone operations to treat morbid obesity were excluded. RESULTS: Intervals between the operation and onset of neuropathy varied from 2 months to 39 years. Most patients did not seem malnourished. Serum concentrations of B vitamins other than thiamine were nearly normal. Symmetric motor-sensory polyneuropathy, predominantly involving the lower limbs, had progressed over intervals varying from 3 days to 8 years. Relative degrees of motor and sensory impairment also varied extensively. Some cases that progressed rapidly mimicked Guillain-Barré syndrome. Electrophysiological and pathological findings were those of axonal neuropathy. Substantial functional recovery from polyneuropathy was seen in most patients by 3 to 6 months after initiating thiamine supplementation. Motor recovery was better than sensory recovery. CONCLUSIONS: Various symptoms were seen in patients with postgastrectomy neuropathy. Thiamine deficiency should be considered in the differential diagnosis of motor-sensory polyneuropathy after gastrectomy.

Painful alcoholic polyneuropathy with predominant small-fiber loss and normal thiamine status.

BACKGROUND: Although polyneuropathy related to chronic alcoholism has been reported frequently, its clinical features and pathogenesis remain to be clarified. OBJECTIVE: To determine the clinicopathologic features and pathogenesis of alcoholic polyneuropathy associated with pain in patients with normal thiamine status, particularly in comparison to beriberi neuropathy. PATIENTS AND METHODS: Clinical, electrophysiologic, and histopathologic findings were assessed in 18 patients with painful alcoholic polyneuropathy and normal thiamine status. RESULTS: Symmetric sensory-dominant polyneuropathy predominantly involving the lower limbs was the major clinical pattern. Painful sensations with or without burning quality represented the initial and major symptom. Progression of symptoms usually was gradual, continuing over months or years. Electrophysiologic and pathologic findings mainly indicated an axonal neuropathy. Densities of small myelinated fibers and unmyelinated fibers were more severely reduced than the density of large myelinated fibers, except in patients with a long history of neuropathic symptoms and marked axonal sprouting. CONCLUSIONS: The clinicopathologic features of painful symptoms and small axon loss are distinct from those of beriberi neuropathy. Sensory-dominant involvement with prominent neuropathic pain is characteristic of alcoholic neuropathy when thiamine deficiency is not involved, supporting the view of direct neurotoxic effect by alcohol or its metabolites.

A novel missense mutation in the early growth response 2 gene associated with late-onset Charcot--Marie--Tooth disease type 1.

A novel mutation (Arg381Cys) in the second zinc-finger domain of early growth response 2 (EGR2) was identified in a late-onset Charcot--Marie--Tooth disease type 1 (CMT1) patient. This patient had initial symptoms of numbness and weakness in the leg at age 59, and a median nerve motor conduction velocity of 27 m/s. A sural nerve biopsy showed a severe loss of myelinated fibers with numerous onion bulbs. This is the first report of the EGR2 mutation presenting a late onset of CMT1 phenotype. Its mutation was a different amino acid substitution at codon 381 (Arg381His) which demonstrated congenital hypomyelinating neuropathy or early-onset CMT1. This report suggests that the EGR2 mutation represents divergent phenotypes at codon 381, which may be a mutation hotspot.

Age of onset influences clinical features of chronic inflammatory demyelinating polyneuropathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP), which can occur through life from childhood to old age, presents a wide variety of clinical phenotypes. We investigated the relationship between age of onset and phenotype in 124 CIDP patients. Clinical symptoms, pathologic findings and electrophysiologic features were assessed according to age at onset: juvenile, younger than 20-years-old; adult, 20 to 64; and elderly, older than 64 (total n=124). Half of the juvenile group showed subacute progression initially, while most patients in the elderly group showed chronic insidious progression (chi(2)=23.2, P<0.0001). Motor dominant neuropathy was prominent in juveniles, while sensorimotor neuropathy was frequent in the elderly group (chi(2)=27.0, P<0.0001). A relapsing and remitting course predominated in the juvenile group (chi(2)=8.50, P=0.0143). Demyelinating and axonal degenerating features in sural nerve biopsy and in nerve conduction studies were common to three age groups. The subperineurial edema was more prominent in the juvenile and adult groups (P=0.006). Functional recovery was common in all three age groups, but was least apparent in the elderly group (P=0.00062). Demyelinating features in studies of nerve conduction and biopsy specimens was common to all three age groups, and was a useful diagnostic feature. Clinical features of CIDP differ by age of onset, which is a factor to consider in diagnosis, therapy, and prognosis.

An axonal form of Charcot-Marie-Tooth disease showing distinctive features in association with mutations in the peripheral myelin protein zero gene (Thr124Met or Asp75Val).

OBJECTIVES AND METHODS: Seven families were studied with an axonal form of Charcot-Marie-Tooth disease (CMT) associated with mutations in the peripheral myelin protein zero (MPZ) gene-Thr124Met or Asp75Val. RESULTS: Patients with these mutations commonly showed relatively late onset sensorimotor neuropathy predominantly involving the lower limbs. Sensory impairment typically was marked, and distal muscle atrophy and weakness were also present in the legs. Adie's pupil and deafness were often present, and serum creatine kinase concentrations were often raised irrespective of which MPZ mutation was present. Relatively well preserved motor and sensory nerve conduction velocities contrasted with reduced or absent compound muscle action potentials and sensory nerve action potentials. Axonal change with marked axonal sprouting was seen in sural nerve specimens. CONCLUSION: The similar associated clinical findings suggest that patients with axonal CMT with an MPZ gene mutation share distinctive clinical features.

Diagnostic implications of elevated levels of smooth-muscle myosin heavy-chain protein in acute aortic dissection. The smooth muscle myosin heavy chain study.

BACKGROUND: A rapid 30-minute assay of circulating smooth-muscle myosin heavy-chain protein has been developed as a biochemical diagnostic tool for aortic dissection. OBJECTIVE: To determine the sensitivity and specificity of this assay. DESIGN: Cross-sectional study. SETTING: 8 major cardiovascular centers in Japan. PATIENTS: 95 patients with acute aortic dissection, 48 patients with acute myocardial infarction, and 131 healthy volunteers. MEASUREMENTS: Levels of circulating smooth-muscle myosin heavy-chain protein. RESULTS: Patients with acute aortic dissection who presented within 3 hours after onset had elevated levels of circulating smooth-muscle myosin heavy-chain protein. In these patients, the assay had a sensitivity of 90.9%, a specificity of 98% compared with healthy volunteers, and a specificity of 83% compared with patients who had acute myocardial infarction; the clinical decision limit was 2.5 microgram/L. All patients with proximal lesions had elevated levels of smooth-muscle myosin heavy-chain protein, and only patients with distal lesions had decreased levels (<2.5 microgram/L). CONCLUSIONS: Levels of smooth-muscle myosin heavy-chain protein can be used to diagnose aortic dissection soon after symptom onset. The assay had the greatest diagnostic value in patients with proximal lesions.

Differential response to corticosteroid therapy of MRI findings and clinical manifestations in spinal cord sarcoidosis.

Spinal cord sarcoidosis is a rare disorder whose natural history and therapeutic outcome are not fully known. We examined four patients with spinal cord sarcoidosis both clinically and radiologically, particularly in relation to corticosteroid treatment. The initial manifestation was cervical myelopathy in three and uveitis in one. All four patients progressed slowly until corticosteroid therapy was initiated. The cervical spine was involved in all patients. Magnetic resonance imaging (MRI) who showed spinal cord swelling with T2-weighted high intensity and linear leptomeningeal and patchy or diffuse intramedullary enhancement with gadolinium diethylene triamine-pentaacetic acid. With corticosteroid therapy, dramatic improvement was seen on MRI, including disappearance or marked reduction of swelling and enhancement. Plasma levels of angiotensin-converting enzyme (ACE) were also markedly improved. In contrast, the clinical symptoms were little improved in one patient, unchanged in two, and rather worsened in one patient. Recurrence was seen on MRI at the maintenance dose in all four patients, without any dramatic change in clinical manifestation. MRI findings and plasma ACE are well correlated with active lesion of the spinal cord sarcoidosis, providing a useful marker for recurrence, but do not parallel the clinical manifestations.

[Two families of Charcot-Marie-Tooth disease with Adie's pupil, axonal neuropahy and the Thr124Met mutation in the peripheral myelin protein zero gene].

We reported two families of Charcot-Marie-Tooth disease (CMT) with Thr124Met mutation in the peripheral myelin protein zero (MPZ). The clinical features of the proband patients of both families showed Adie's pupil, severe sensory dominant neuropathy in lower extremities, and axonal changes in sural nerve biopsies and nerve conduction studies. Muscle atrophy and weakness was mild in the lower legs, while sensory impairment was marked. The proband patient of family 1 had four symptomatic siblings and one of them showed Adie's pupil. The elderly daughter of the proband of family 2 showed Adie's pupil and younger daughter showed photophobia. The biopsied sural nerves of both proband patients revealed prominent axonal sprouting, and sub-perineurial edema and mild fascicular enlargement. Segmental demyelination was not frequent in teased fiber assessment. The present two family cases strongly suggest that this MPZ gene mutation (Thr124Met) could be present among the patients with CMT type 2, axonal form. Furthermore, the patients showing sensory neuropathy and Adie's pupil may need to be reexamined with this mutation. It is also necessary to reassess genotype-phenotype correlation in CMT patients particularly in reference to type 1 and type 2.

Late-onset familial amyloid polyneuropathy type I (transthyretin Met30-associated familial amyloid polyneuropathy) unrelated to endemic focus in Japan. Clinicopathological and genetic features.

Clinicopathological and genetic features were assessed on 35 Japanese families affected by late-onset familial amyloid polyneuropathy type I (transthyretin Met30-associated familial amyloid polyneuropathy, FAP TTR Met30) whose siblings were unrelated to endemic Japanese foci. In these patients (50 years or older), the most common initial symptom was paraesthesias in the legs. Autonomic symptoms were generally mild and did not seriously affect daily activities. The male-to-female ratio was extremely high (10.7 : 1). A family history was evident in only 11 out of 35 families, and other patients were apparently sporadic. The rate of penetrance was very low. Symptomatic siblings of familial cases showed a late age of onset, male preponderance and clinical features similar to those of the probands. Asymptomatic carriers, predominantly female, were detected relatively late in life. The geographical distribution of these late-onset, FAP TTR Met30 cases was scattered throughout Japan. In three autopsy cases and 20 sural nerve biopsy specimens, neurons in sympathetic and sensory ganglia were relatively preserved. Amyloid deposition was seen in the peripheral nervous system, particularly in the sympathetic ganglia, dorsal root ganglia and proximal nerve trunks such as sciatic nerve. These abnormalities were milder than those seen in typical early-onset FAP TTR Met30, as observed in two Japanese endemic foci of this disease. While axonal degeneration was prominent in myelinated fibres, resulting in severe fibre loss, unmyelinated fibres were relatively preserved. Our cases of late-onset FAP TTR Met30 showed features distinct from those of typical early-onset FAP TTR Met30 that occurred in the two Japanese endemic foci. Factors responsible for clinicopathological differences between these two forms of FAP TTR Met30 need to be identified.

Axonal and perikaryal involvement in chronic inflammatory demyelinating polyneuropathy.

OBJECTIVES: To assess the extent of loss of myelinated nerve fibres and spinal motor neuron loss in chronic inflammatory demyelinating polyneuropathy (CIDP), a clinicopathological study was conducted on biopsied sural nerves and necropsied spinal cords from patients with CIDP. METHODS: The myelinated fibre pathology of 71 biopsied sural nerves and motor neuron pathology of nine necropsied spinal cords at L4 levels in patients with CIDP were quantitatively and immunohistochemically assessed. RESULTS: Myelinated nerve fibre density was significantly diminished to 65.4% of the control values (p <0.0001), correlating inversely with the extent of segmental demyelination and remyelination (r = -0.43, p < 0.0005) and duration of illness (r = -0.31, p < 0.01). Numbers of large spinal motor neurons in CIDP were variably but significantly diminished (range from 46.0 to 97.6% of the age matched control value (p < 0.005)), and reactive astrogliosis was evident in the ventral horn in CIDP. The frequency of ventral horn neurons exhibiting central chromatolysis and the accumulation of phosphorylated high molecular weight neurofilament protein was significantly higher in CIDP than in controls (p<0.01 and p<0.05). CONCLUSIONS: The loss of nerve axons and spinal motor neurons is common in CIDP, and extensive in some cases. These neuronal and axonal losses may influence the functional prognosis in CIDP.

Anti-GQ1b ganglioside antibody and ophthalmoplegia of undetermined cause.

BACKGROUND/AIM: Serum antibody against ganglioside GQ1b is reported to be closely associated with immune mediated ophthalmoplegia in the Fisher and Guillain-Barré syndromes. Its presence against glycolipids, in particular ganglioside GQ1b, was investigated in patients with ophthalmoplegia of unknown origin. METHODS: 16 patients with ophthalmoplegia, the cause of which could not be confirmed from clinical findings or diagnostic testing, were tested. 34 patients who had ophthalmoplegia of definite cause, 16 healthy people, and 23 patients with typical Fisher syndrome served as the controls. The ELISA was used to check for serum antibodies against glycolipids in all study participants. RESULTS: Two of the 16 patients with ophthalmoplegia of unknown cause had serum IgG antibody against GQ1b but not against other glycolipids, and 22 of the 23 patients with typical Fisher syndrome had this antibody. No anti-GQ1b antibodies were found in the patients with ophthalmoplegia of definite cause or in the normal controls. CONCLUSION: A common underlying cause appears to bring about the pathogenesis of palsy in Fisher syndrome and in the ophthalmoplegia with positive anti-GQ1b IgG antibody, called atypical Fisher syndrome. This antibody may prove a useful clinical marker for differentiating Fisher syndrome, typical and atypical, in patients with ophthalmoplegia.

[Pitfalls in echocardiographic diagnosis of mitral bileaflet prolapse].

Preoperative echocardiography provides good planning information for successful repair of mitral valve regurgitation, but identifying the prolapse of both the anterior and posterior leaflets is sometimes difficult. To clarify the cause of this problem, preoperative echocardiographic findings and intraoperative observations of the prolapse were analyzed in 124 patients with non-rheumatic pure mitral regurgitation. In 48 patients with final diagnoses of bileaflet prolapse, 16 (33%) were considered to have only single leaflet prolapse before the operation. Anterior leaflet prolapse was overlooked in 14, and prolapse of either of its commissural segments was the least detectable by echocardiography. Chordal rupture was seen more in the posterior leaflet than in the anterior leaflet. Movement of the anterior leaflet may be influenced by a prolapsed and hypermobile posterior leaflet and/or regurgitant jet flow caused by the posterior leaflet prolapse.