blue lunula in Wilson’s disease), as can the heart and
In addition to movements, other information can be
gleaned from the eye during an examination, such as
the presence of a sunflower cataract (which may suggest
Wilson’s disease), a cherry-red spot on the retina (
siali-dosis), or choreoretinitis with maculopathy and optic
atrophy (eg, subacute sclerosing panencephalitis).
During the neurologic examination, neurologists can
assess behavior, language, cranial nerves, upper and
lower motor neuron signs, eye movement disorders
(eg, opsoclonus, oculogyric crisis, oculomotor apraxia,
and supranuclear gaze palsies), and the phenomenology, distribution, and timing of movement disorders.
In addition, a sensory exam may be useful. Parkinsonism with pure dorsal column sensory abnormalities, for
example, is characteristic of POLG1 mutations.
Many laboratory tests are available, and neurologists
should use them selectively. As a visiting professor, Dr.
Lang sees many patients who have undergone unneces-
sary tests. “Do not use a shotgun approach,” Dr. Lang
said. “Be focused. Use them intelligently.”
Various metabolic pathways can be altered in pa-
tients with inborn errors of metabolism, thus creating
risk of decompensation. Tests for patients suspected
of having an inborn error of metabolism may include
blood gases, anion gap, ammonia, glucose, lactate, uric
acid, creatine kinase, amino acids, insulin, urine organic
acids, ketones, and reducing substances.
Blood can be tested for heavy metals, vitamin de-ficiencies, and antibodies. CSF testing may be invaluable, including real-time quaking-induced conversion
in patients with a suspected prion disorder or, when
warranted, evaluation for extremely rare disorders such
as testing for folate in patients with suspected cerebral
Tissue biopsies, EEG, and electroretinogram may
reveal useful information, and movement disorders
laboratory testing, including assessments for functional
movement disorder studies (eg, back-averaging) can
help diagnose selected conditions, including psychogenic movement disorders.
Neurologists should be comfortable looking at neuro-
imaging to identify patterns of atrophy, the presence of
heavy metals, or the occurrence of calcium, for example.
Some rare movement disorders require vascular imag-
ing. “Unexpected normal findings should be a clue as
well,” he said. Dr. Lang described a patient who was
thought to have cerebral palsy, but the patient’s MRI
was normal. The patient ultimately was found to have
Basal ganglia lesions and recurrent episodes of encephalopathy may indicate that a patient has biotin-re-sponsive basal ganglia disease. “This is a critical disorder
for us to recognize,” Dr. Lang said, because a patient
who is treated early enough with biotin and thiamine
can make a striking recovery.
Punctate changes throughout the posterior fossa, the
cerebellum, and the pons, as well as other regions, are
characteristic of a vascular abnormality called chronic
lymphocytic inflammation with pontine perivascular
enhancement responsive to steroids (CLIPPERS), which
can be treated with prednisone.
Genetic testing can help establish a diagnosis, but even
in careful studies, whole exome sequencing may fail to
provide a diagnosis in more than 40% of cases.
Problems with next-generation sequencing include
incidental findings, variants of unknown significance,
and the possibility of patients having two or more concomitant diseases or incompletely penetrant pathogenic
variants. In addition, clinical exome sequencing does
not detect repeat expansion disorders, copy number
variations, structural variants, or abnormalities in the
noncoding part of the genome.
A recently published case report further highlights
the need for clinical expertise amid advances in genetic
testing, Dr. Lang said. Zittel et al reported a case of a
patient who came to a clinic with genetic test results
showing that she had GCH1 and TH mutations. Clinically, however, neurologists determined that she had a
Tissue biopsies, EEG,
electroretinogram, and movement
disorder laboratory testing may
reveal useful information that can
help diagnose selected conditions.