Longitudinal quantitative magnetic resonance imaging in adrenomyeloneuropathy.

BACKGROUND AND PURPOSE: Adrenomyeloneuropathy (AMN) is the most frequent metabolic hereditary spastic paraplegia. Accordingly, its main site of pathological changes is the spinal cord. It is difficult to quantify AMN progression because commonly used clinical scales have limitations and reliable biomarkers are lacking. The goal was to investigate whether spinal cord and brain quantitative magnetic resonance imaging may assess structural changes in AMN over a relatively short time period. METHODS: In this longitudinal observational study, the total cord areas (TCAs) from the C2-C3 to T2-T3 level and diffusion tensor imaging (DTI) metrics of the cervical spinal cord and brain portion of the corticospinal tracts in six AMN and six age-matched control subjects at baseline and at a mean follow-up of 22.6 months were assessed. RESULTS: A significant reduction of the mean TCA at the T1-T2 level (-3.79%) and a trend of reduction at the lowest cervical levels were observed only in AMN patients. Additionally, DTI metrics revealed significant changes in fractional anisotropy (-8.84%), mean diffusivity (+12.62%) and radial diffusivity (+25.91%) at the C2-C3 level. DISCUSSION: The study encourages the assessment of TCAs and spinal cord DTI metrics as surrogate outcome measures in AMN, by focusing on the cervical-thoracic junction and the uppermost part of the cervical spinal cord. Despite the limitation of the results due to the small number of investigated subjects, these observations are useful for forthcoming clinical trials in AMN and possibly other hereditary diseases with predominant spinal cord involvement.

Combined central and peripheral demyelination: Clinical features, diagnostic findings, and treatment.

Combined central and peripheral demyelination (CCPD) is rare, and current knowledge is based on case reports and small case series. The aim of our study was to describe the clinical features, diagnostic results, treatment and outcomes in a large cohort of patients with CCPD. Thirty-one patients entered this retrospective, observational, two-center study. In 20 patients (65%) CCPD presented, after an infection, as myeloradiculoneuropathy, encephalopathy, cranial neuropathy, length-dependent peripheral neuropathy, or pseudo-Guillain-Barré syndrome. Demyelinating features of peripheral nerve damage fulfilling European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) electrodiagnostic criteria for CIDP were found in 23 patients (74%), and spatial dissemination of demyelinating lesions on brain MRI fulfilling the 2010 McDonald criteria for multiple sclerosis (MS) in 11 (46%). Two thirds of the patients had a relapsing or progressive disease course, usually related to the appearance of new spinal cord lesions or worsening of the peripheral neuropathy, and showed unsatisfactory responses to high-dose corticosteroids and intravenous immunoglobulins. The clinical presentation of CCPD was severe in 22 patients (71%), who were left significantly disabled. Our data suggest that CCPD has heterogeneous features and shows frequent post-infectious onset, primary peripheral nervous system or central nervous system involvement, a monophasic or chronic disease course, inadequate response to treatments, and a generally poor outcome. We therefore conclude that the current diagnostic criteria for MS and CIDP may not fully encompass the spectrum of possible manifestations of CCPD, whose pathogenesis remains largely unknown.

Adult polyglucosan body disease: clinical and histological heterogeneity of a large Italian family.

Adult Polyglucosan Body Disease (APBD) is a rare inherited leukodystrophy associated with axonal polyneuropathy, mainly reported in persons of Ashkenazi-Jewish descent. We describe three Italian siblings at disease onset, presenting in their fifties with a combination of pyramidal and ataxic signs, mild demyelinating neuropathy on neurophysiological investigation (1/3 cases) and transient symptoms (1/3). A leucoencephalopathy with infratentorial lesions without enhancement and medullary/spine atrophy was demonstrated on brain/spine MRI (3/3). Muscle biopsy was normal in 2/3; both muscle and nerve biopsy showed polyglucosan bodies in the sibling with polyneuropathy. This indicated a need for GBE1 sequencing, which revealed a novel missense mutation (c.1064G>A; p.Arg355His) and one previously described (c.1604A>G; p.Tyr535Cys) in all siblings. We highlight that peripheral neuropathy, deemed as disease hallmark, may be missing and that transient symptoms are confirmed as early disease manifestations. The pattern of damage at neuro-imaging described recurs irrespective of clinical presentation, constituting a unifying diagnostic clue.

Adult polyglucosan body disease in a patient originally diagnosed with Fabry's disease.

Adult polyglucosan body disease is a rare autosomal recessive disease, caused by glycogen branching enzyme gene mutations, characterised by urinary dysfunction, spastic paraplegia with vibration sense loss, peripheral neuropathy, and cognitive impairment. Fabry's disease is an X-linked lysosomal storage disorder caused by α-galactosidase A gene mutations; neurological manifestations include cerebrovascular accidents, small-fibre neuropathy and autonomic dysfunction. Here, we report the case of a 44-year-old Sicilian male with stroke-like episodes, hypohidrosis and mild proteinuria, which led to the diagnosis of Fabry's disease after a hemizygous mutation (p.Ala143Thr) in α-galactosidase A gene was detected. Subsequently, he developed progressive walking difficulties and dementia, which were considered atypical for Fabry's disease. Therefore, we performed additional investigations that eventually led to the diagnosis of adult polyglucosan body disease caused by two novel missense mutations (p.Asp413His and p.Gly534Val) in the glycogen branching enzyme gene. Recently, the pathogenic role of the p.Ala143Thr mutation in causing Fabry's disease has been questioned. This case underlines the importance of performing further investigations when facing with atypical features even in the presence of a genetic diagnosis of a rare disease.

Pendular nystagmus in hypomyelinating leukodystrophy.

We report the case of a 49-year old woman affected by hypomyelinating leukodystrophy. She presented with typical pendular nystagmus that was analyzed with video-oculography which is provided in the supplementary material of the report. The pendular nystagmus was accompanied by upper limb ataxia on the index-to-nose test. The video was partly recorded with a slow-motion technique in order to better demonstrate the ataxia and the pendular nystagmus. The brain MRI demonstrated a characteristic pattern of hypomyelination. Pendular nystagmus is a key clinical sign that contributes to the diagnosis of CNS hypomyelination when a leukodystrophic pattern is observed on brain MRI.

Late-onset sporadic ataxia, pontine lesion, and retroperitoneal fibrosis: a case of Erdheim-Chester disease.

A 60-year-old man with progressive gait ataxia and mild pyramidal signs showed at MRI a pontine lesion with post-contrast enhancement in the left middle cerebellar peduncle. Diagnosis of Erdheim-Chester disease (ECD), a rare non-Langerhans cell histiocytosis, was suggested, further supported by a previously diagnosed retroperitoneal fibrosis. X-ray films demonstrated characteristic bilateral and symmetric osteosclerosis of the long bones of the lower limbs, which at radionuclide studies exhibited a marked increase in technetium-99 uptake. A cerebral 18FDG-PET showed a relevant pontine uptake of the tracer. Re-evaluation of a past retroperitoneal biopsy showed an intense CD68+, CD1a-, and S100- infiltrate of histiocytes with foamy cytoplasm, thus confirming the diagnosis. ECD should be regarded as a rare cause of adult-onset sporadic ataxia, especially when pontine lesions and extraneurological manifestations are present.

Reliability of clinical outcome measures in Charcot-Marie-Tooth disease.

We assessed inter- and intra-rater reliability of outcome measures in Charcot-Marie-Tooth disease (CMT) patients. In 40 CMT patients, we assessed reliability of Overall Neuropathy Limitations Scale (ONLS), 10-m timed walk (T10MW), 9-hole-peg test (9-HPT), maximal voluntary isometric contraction (MVIC) of arm (elbow flexion, hand-grip, and three-point pinch) and leg (knee extension, foot dorsiflexion/plantar flexion). Reliability was substantial for ONLS, excellent for T10MW and 9-HPT. For MVIC, inter and intra-rater reliability was excellent for hand contractions; for leg contractions, intra-rater agreement was moderate to substantial, whereas inter-rater agreement was poor. An ad hoc device was produced to immobilize the foot and MVIC reliability was re-assessed in 26 CMT patients, resulting in excellent inter-rater and intra-rater reliability for foot dorsiflexion, and clear inter-rater improvement for foot plantar flexion. All outcome measures appear adequate for CMT assessment. Use of an immobilization device improves foot MVIC reliability, preventing biased findings in patients with greater strength.