Leading clue | Syndromic features (especially early) | Candidate diagnoses | Key investigations | |
Sporadic | Genetic* | |||
Unusual | ||||
Socioemotional decline leading | Reduced empathy, disinhibition, apathy, obsessionality, stereotypies, altered eating behaviour, executive deficits; atypical parkinsonism (progressive supranuclear palsy/corticobasal syndrome) frequent later | Behavioural variant frontotemporal dementia | C9orf72, GRN, MAPT, others less commonly | MRI (figure 2), but atrophy highly variable and may be subtle, may have associated midbrain atrophy (progressive supranuclear palsy), genetics |
Language decline leading | Effortful, misarticulated, apraxic speech, binary reversals, grammatical errors, orofacial apraxia; atypical parkinsonism (progressive supranuclear palsy/corticobasal syndrome) frequent later | Non-fluent primary progressive aphasia | GRN, C9orf72, others (uncommon) | MRI (figure 2), but atrophy variable; genetics if young/suspicious family history |
Loss of vocabulary, severe anomia with impaired single word comprehension despite fluent well-structured speech, often frontotemporal dementia-like behaviours | Semantic primary progressive aphasia | MAPT, others (rarely) | MRI (figure 2) characteristic | |
Anomia/word-finding pauses, phonemic errors, phrase repetition/verbal working memory deficits | Logopenic aphasia (usually Alzheimer pathology) | GRN (rarely) | MRI asymmetric (predominantly left-sided) temporoparietal atrophy, CSF Alzheimer markers | |
Visuospatial decline leading | Difficulty reading unusual fonts/night driving/using gadgets, mispositioning items; later apperceptive agnosia/disorientation, dyscalculia, anomia | Posterior cortical atrophy (usually Alzheimer pathology; some dementia with Lewy bodies, others) | MRI (figure 2), CSF Alzheimer markers | |
‘Frontal’—ataxia | Also urinary urgency/incontinence | Normal-pressure hydrocephalus† | MRI ventriculomegaly and associated features | |
May have history of prior neurological episodes | Multiple sclerosis (especially primary/secondary progressive) | MRI (brain/cord) demyelination features, CSF unmatched oligoclonal bands | ||
History of cranial irradiation (often delayed), also pyramidal/other neurological signs | Post-irradiation vasculopathy | MRI extensive white matter damage | ||
Rapid‡ | Early widespread cognitive impairment (often prominent visual dysfunction), myoclonus/other neurological signs | Creutzfeldt-Jakob disease (classically), Alzheimer’s disease, dementia with Lewy bodies (uncommonly) | Prion (Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker, familial fatal insomnia, others)§ | MRI cortical/basal ganglia signal change, EEG (periodic complexes—Creutzfeldt-Jakob disease), CSF (RT-QuIC, Alzheimer markers), DAT (?dementia with Lewy bodies), genetics |
Frontotemporal dementia plus deltoid/triceps fasciculations, pyramidal signs | Frontotemporal dementia–motor neurone disease | C9orf72 | MRI, EMG (often normal), genetics | |
Behavioural variant frontotemporal dementia-like plus corticobasal syndrome, atypical parkinsonism, young, markedly obsessive/stereotypical behaviour | Frontotemporal dementia (FUS-opathy)¶ | MRI marked caudate atrophy | ||
Headache, fluctuation, seizures, systemic features | Vasculitis (CNS/systemic)† | MRI, CT angiogram, CSF pleocytosis, autoantibodies/inflammatory markers; consider brain biopsy | ||
Seizures, jerks, dyskinesias, fluctuation, neuropsychiatric/autonomic/systemic features | Limbic encephalitis† | MRI high signal in hippocampi/mesial temporal lobe, autoantibodies, whole body-PET/neoplasia screens | ||
Executive/behavioural decline with gait disturbance/variable other neurological features | Tumour (eg, lymphoma), subdural haematoma, other space-occupying lesions† | MRI mass/gadolinium enhancement, may have non-CNS primary, may need brain biopsy | ||
Immunosuppressed, compatible history of infection | Human immunodeficiency virus, human herpes viruses, progressive multifocal leukoencephalopathy, tuberculosis, syphilis, Whipple’s disease, fungal†; subacute sclerosing panencephalitis | MRI abnormal signal/gadolinium enhancement, blood/CSF serology | ||
Toxic exposure/dietary deficiency states | Alcohol usually nutritional, especially thiamine (Wernicke-Korskakoff syndrome); heroin/other drug abuse, lithium toxicity/ iatrogenic, metals† | MRI various patterns with white/grey matter involvement, abnormal signal; drug, metabolic, metal screens | ||
Young adult,** neurological | Ataxia | Paraneoplastic†, superficial siderosis | Spinocerebellar ataxias, Niemann-Pick C, fragile X, mitochondrial, dentatorubral pallidoluysian atrophy, Kufs’ disease, prion | This group in general requires specialist consultation—principles are (1) definition of phenotype with brain MRI, plus CSF/electrophysiology, depending on presentation; (2) blood screens (metabolic/inflammatory) and/or genetics directed to cause; (3) tissue biopsy if required for diagnosis (especially muscle/axillary skin for storage diseases, etc) |
Akinetic–rigid | Huntington’s disease, Wilson’s disease,† neurodegeneration with brain iron accumulation (various) | |||
Autonomic | Sarcoidosis† | Porphyria, adrenoleukodystrophy, hereditary sensory and autonomic neuropathy 1E, familial fatal insomnia | ||
Buccolingual mutilation | Neuroacanthocytosis, Lesch-Nyhan | |||
Chorea/dystonia | Antiphospholipid, rheumatological† | Huntington’s disease, Wilson’s disease,† neuroacanthocytosis, neuronal brain iron accumulation disorders, dentatorubral pallidoluysian atrophy, Kufs’ disease (especially facial) | ||
Deafness (peripheral) | Susac’s syndrome,† Behçet’s disease,† siderosis, sarcoidosis† | Mitochondrial, hereditary sensory and autonomic neuropathy 1E | ||
Eye abnormalities | Behçet’s disease, sarcoidosis, Susac’s syndrome† | Kayser-Fleischer rings: Wilson’s disease† Cataract: cerebrotendinous xanthomatosis†, myotonic dystrophy, mitochondrial Retinopathy: mitochondrial | ||
Gaze palsy | Chronic meningitides (inflammatory/neoplastic)† | Gaze apraxia: Huntington’s disease Supranuclear gaze palsy: (vertical) Niemann–Pick C, (horizontal) spinocerebellar ataxia type 2, Gaucher’s† External ophthalmoplegia: mitochondrial | ||
Peripheral neuropathy | Sarcoidosis† | Mitochondrial, neuroacanthocytosis, Fabry’s,† spinocerebellar ataxias, metachromatic leukodystrophy, adrenoleukodystrophy, hereditary sensory and autonomic neuropathy 1E, cerebrotendinous xanthomatosis,† porphyria† | ||
Pyramidal signs | Spinocerebellar ataxias, familial AD (especially PS1), adrenoleukodystrophy, Krabbe’s | |||
Seizures (especially myoclonic) | Poor control, anticonvulsants† | Mitochondrial, dentatorubral– pallidoluysian atrophy, Lafora body disease, Kufs’ disease, other progressive myoclonic epilepsies | ||
Strokes | Antiphospholipid syndrome† | CADASIL, cerebral amyloid angiopathies (familial), Fabry’s† | ||
Systemic | Hepatic/gastrointestinal | Hepatic encephalopathy† | Wilson’s disease,† Gaucher’s,† mitochondrial, porphyria† | |
Musculoskeletal abnormalities | Rheumatological† | Paget’s disease, inclusion body myopathy: VCP
Tendon xanthomas: cerebrotendinous xanthomatosis† Bone cysts: polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy | ||
Renal impairment | Uraemic encephalopathy† | Fabry’s,† mitochondrial | ||
Skin abnormalities | Behçet’s disease, rheumatological† | Fabry’s† | ||
Splenomegaly | Niemann-Pick C, Gaucher’s† |
This list is not exhaustive.
*Family history suggesting autosomal dominant or maternal inheritance in successive generations is particularly helpful but may be censored or absent (these patients also tend to be younger).
†Potentially treatable process.
‡Slower onset may also occur in some cases
§Although genetic prion diseases tend to be rapid, some present indolently.
¶Can be suspected but not presently confirmed during life.
**Leading features, not covered above —these tend to be the most striking features but various combinations occur.
CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CNS, central nervous system; C9orf72, mutation of chromosome 9 open reading frame 72; CSF, cerebrospinal fluid; DAT, dopamine transporter scan; EEG, electroencephalogram; EMG, electromyogram; FUS, fused-in-sarcoma protein; GRN, progranulin gene mutations; MAPT, microtubule associated protein tau mutations; PET, positron emission tomography; PS1, presenilin 1; RT-QuIC, real-time quaking-induced conversion prion protein detection; VCP, valosin-containing protein gene mutation.