Table 3.
Some syndromes with peripheral or subcortical hearing impairment and dementia
| Disease | Aud | Cogn | Associated features | Diagnostic investigations |
|---|---|---|---|---|
| Inflammatory | ||||
| Antiphospholipid syndrome [108] | F; C, RCa | F | Headache, seizures, chorea, myelopathy, optic neuritis, vestibulopathy | Antibody profile with compatible clinical phenotype |
| Multiple sclerosis [109] | U; RCa | Fb | Diverse: vertigo, optic neuritis, various brainstem, cerebral, spinal signs | Compatible clinical and MRI features of CNS demyelination, (McDonald criteria), supported by CSF unmatched oligoclonal bands |
| Neuro-Behçet’s [110] | F; RCa | Uc | Vestibulopathy, uveitis, headache, brainstem signs, hemiparesis, cerebral venous thrombosis; oral/genital ulcers | None specifically; International Study Group criteria (with pathergy test) for systemic disease |
| Neurosarcoidosis [111] | U; RCa | F | Vestibulopathy, cranial nerve palsies, seizures, aseptic meningitis, myelopathy, peripheral neuropathy, pituitary dysfunction | Contrast MRI sensitive but not specific; whole body PET, biopsy involved peripheral tissue |
| Susac’s syndrome [112] | T; Ca,d | T | Retinal artery occlusions; migraine, ataxia, vertigo, long tract signs | MRI (callosal ‘snowball’ lesions); retinal fluoroscein angiography (multifocal distal arteriolar occlusions) |
| Infectious | ||||
| Cryptococcal meningitis [113] | U; RCa | F | Headache, papilloedema, seizures, vestibulopathy, cranial nerve palsies; more common in immunocompromised patients | CSF Cryptococcal antigen |
| Neuroborreliosis [114] | U; RCe | Uf | Lymphocytic meningitis with cranial palsies, vestibulopathy | Lyme serology |
| Neurosyphilis [115] | U; RCa,g | T | Chorioretinitis, Argyll Robertson pupils, vestibulopathy, cranial nerve palsies and brainstem signs, myelopathy (tabes dorsalis), brain infarcts | Treponemal serology (blood and CSF) |
| Genetic | ||||
| CADASIL [116] | U; Ca | T | Migraine, stroke, psychiatric disturbance | Characteristic MRI with marked anterior temporal/external capsule white matter involvement Notch3 mutations |
| MELAS/other mitochondrial syndromes [117] | T/F; C | T/F | Migraine, seizures, stroke-like episodes, ophthalmoplegia, myopathy, lactic acidosis, diabetes mellitus | Various mitochondrial DNA mutations |
| HSAN IE [118] | T; C, RC?h | T | Sensory and autonomic neuropathy, optic neuropathy, narcolepsy | DNMT1 mutations |
| IBMPFD [119] | U; RC? | T | Frontotemporal dementia with inclusion body myositis, Paget’s disease of bone | VCP mutations |
| Niemann-Pick type C [120] | F; RC | Tc | Ataxia, supranuclear gaze palsy, dystonia, psychiatric features, cataplexy, seizures, splenomegaly | Skin fibroblast studies (accumulation of unesterified cholesterol), genotyping |
| Oculo-leptomeningeal amyloidosis [121] | F; RC?a | F | Seizures, stroke-like episodes, headache, ataxia, myelo-radiculopathy, subarachnoid haemorrhage, ocular amyloid | Abnormal meningeal enhancement on contrast MRI Transthyretin mutations |
| Refsum disease [122] | F; RC | U | Retinitis pigmentosa, anosmia, polyneuropathy | Raised plasma phytanic acid PHYH mutation |
| Spinocerebellar ataxias: [83] | F; C, RCi | F | Truncal/limb ataxia, bulbar deficits, proprioceptive impairment, neuropathy, variably prominent across group | Various mutations (most frequently, trinucleotide repeat expansions) |
| Friedreich’s ataxia [123] | Cardiomyopathy, diabetes mellitus (adult onset milder) | FXN expansions | ||
| SCA13 [124] | Gait/limb ataxia, dysarthria, hyperreflexia, vibration sense loss | KCNC3 mutations | ||
| Wolfram’s syndrome [125] | T; RC | Fj | Optic atrophy, diabetes | WFS1 mutations |
| Other | ||||
| Prion diseases [126] | U; RC | T | Rapid neurological decline, often with prominent myoclonus and ataxia | Increased cortical/basal ganglia signal on DWI/FLAIR MRI with compatible clinical phenotype; rarely prion gene mutation (E200K) |
| Superficial siderosis [127] | T; RCk | F | Cerebellar ataxia, pyramidal signs, bladder dysfunction, anosmia, anisocoria; may have history compatible with chronic subarachnoid bleeding | Haemosiderin rimming brain/spinal cord on susceptibility-weighted MRI |
CADASIL cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CJD Creutzfeldt-Jakob disease, DNMT1 DNA cytosine-5-methyltransferase 1 gene, DWI/FLAIR diffusion weighted/fluid-attenuated inversion recovery sequences, FXN frataxin gene, HSAN IE hereditary sensory and autonomic neuropathy with dementia and hearing loss type IE, IBMPFD inclusion body myositis with Paget’s disease of bone and frontotemporal dementia, KCNC3 potassium channel Kv3.3 gene, MELAS mitochondrial encephalopathy with lactic acidosis and stroke-like episodes, PHYH phytanoyl-CoA 2-hydroxylase gene, VCP valosin containing protein gene, WFS1 wolframin gene
The Table excludes paediatric disorders that do not also present during adult life; auditory (Aud) and cognitive (Cogn) phenotypes have been classified according to whether clinical impairments of hearing and/or cognition are: T typical of the entity (a very frequent or defining feature), F frequent (a common association), U unusual (a recognised association). The cognitive phenotype in most cases is not diagnostic, comprising variably prominent executive, subcortical and behavioural deficits and affective changes. The auditory phenotype has been classified according to the origin of hearing loss, where (often limited) information available: C cochlear, RC retrocochlear (auditory nerve and/or brainstem pathways)
aMay be sudden
bGenerally more significant in progressive forms
cMay have prominent neuropsychiatric changes
dLow-to-mid-frequency loss characteristic
eMay have persistent post-treatment altered hearing (e.g., loudness intolerance)
fSubjective cognitive symptoms frequent
gMénière’s-like presentations may occur
hMid-frequency loss
iAuditory brainstem pathway involvement appears more functionally significant than more peripheral involvement and may disrupt temporal processing leading to deficits of spatial and speech perception (frequency of impairment varies with mutation)
jMay be more prominent in later disease
kPrimary cochlear damage may also contribute