RESIDENT & FELLOW SECTION Clinical Reasoning: Section Editor An 82-year-old man with worsening gait John J. Millichap, MD Sheena Chew, MD SECTION 1 neck and left leg cramps. He denied bowel or bladder Ivana Vodopivec, MD, An 82-year-old man with hypothyroidism presented symptoms. PhD with difficulty walking. The patient was previously healthy, playing com- Aaron L. Berkowitz, MD, One year prior to presentation, he noticed that his petitive sports at the national level into his late 70s. PhD legs occasionally “froze” when initiating walking. His His only medication was levothyroxine. gait progressively worsened over the year. He devel- oped balance difficulty, tripping and falling twice Question for consideration: Correspondence to without loss of consciousness. In the 4 months prior Dr. Chew: to presentation, he started using a cane, a rolling 1. What examination findings would help to localize [email protected] walker, then a wheelchair. He reported occasional the etiology of his abnormal gait? GO TO SECTION 2 From the Department of Neurology, Brigham and Women’s Hospital (S.C., I.V., A.L.B.), and Department of Neurology, Massachusetts General Hospital (S.C.), Harvard Medical School, Boston. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. e246 © 2017 American Academy of Neurology ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. SECTION 2 arm dysdiadochokinesia and right leg dysmetria, but The neurologic basis of gait spans the entire neuraxis, no left-sided or truncal ataxia. He could bicycle his requiring assessment of sensory (visual, vestibular, legs in bed and march in place while sitting, but could proprioceptive), motor, and higher-order control not stand without assistance. Once standing, he could (frontal lobes, basal ganglia, brainstem, cerebellum) not begin to walk unless an object was placed on the systems. ground for him to step over. Once he began walking, Our patient’s mental status, cranial nerve, he continued slowly with small steps, but no further strength, sensory, and reflex examinations were nor- freezing. mal. There was no tremor, hypomimia, scanning Question for consideration: speech, hypophonia, or bradykinesia. He had mild resistance to passive movement in his left leg, without 1. What is the localization and differential diagnosis spasticity, rigidity, or contracture. There was right based on the patient’s history and examination? GO TO SECTION 3 Neurology 89 November 21, 2017 e247 ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. SECTION 3 impairment (NPH). Although he did not have supra- Our patient’s history and examination were notable nuclear vertical gaze palsy or impaired vertical for subacute development of freezing of gait and cer- saccades to suggest classic PSP, the pure akinesia with ebellar ataxia. gait freezing variant of PSP can present with isolated Freezing of gait is characterized by sudden, brief freezing of gait. periods of difficulty initiating or continuing locomo- Subacute cerebellar ataxia can be immune- tion, with inability to lift the foot from the floor mediated (associated with anti-Yo, Hu, Tr, Ri, despite normal leg strength. It can occasionally be Ma2, GAD65, calcium and potassium channel anti- overcome with visual cues and is thought to be caused bodies2; Hashimoto encephalopathy), neoplastic, by deficits in functional networks involving the fron- toxic (e.g., alcohol, antiepileptics, heavy metals), tal lobes, basal ganglia, brainstem, and dorsomedial infectious (e.g., progressive multifocal leukoencephal- cerebellar locomotor region.1 opathy due to JC virus), prion diseases (such as Freezing of gait is associated with parkinsonism. It Gerstmann-Sträussler-Scheinker), or metabolic (e.g., can occur in idiopathic Parkinson disease (PD), vitamin E deficiency, hepatocerebral degeneration). atypical parkinsonian syndromes such as multiple Of these conditions, cerebellar ataxia and parkinso- system atrophy (MSA, which may also be associated nian symptoms (such as the freezing of gait seen in with cerebellar ataxia), progressive supranuclear palsy our patient) can co-occur in GAD65 autoimmunity, (PSP), and corticobasal syndrome (CBS), as well as hepatocerebral degeneration, and prion disease. secondary parkinsonism (e.g., due to vascular disease Parkinsonian symptoms and ataxia can also co-occur or normal pressure hydrocephalus [NPH]). Our in spinocerebellar ataxia types 2, 3, 6, 8, and 17,3 patient’s symptoms progressed more rapidly than is though these inherited diseases tend to present at typical for these disorders, and he lacked key features a younger age than in our patient, who also had no of these diagnoses, such as tremor or bradykinesia family history of neurologic disease. (PD), autonomic abnormalities such as orthostatic Question for consideration: hypotension (MSA), cortical findings such as alien limb phenomenon, speech or motor apraxia, or 1. What diagnostic studies should be performed to cortical sensory loss (CBS), or cognitive or bladder narrow the differential diagnosis? GO TO SECTION 4 e248 Neurology 89 November 21, 2017 ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. SECTION 4 evaluate for underlying malignancy. His basic CSF Our patient’s serum complete blood count, compre- measures and PET/CT were normal. However, hensive metabolic panel, liver function tests, antinu- CSF electrophoresis revealed a monoclonal (M) clear antibody, thyroid function tests, antithyroid spike in the absence of a similar pattern on serum peroxidase, vitamin E, and vitamin B12 were normal. electrophoresis, indicating intrathecal antibody Brain MRI was normal, as was brain PET (performed production. to look for metabolic signatures of neurodegenera- One month after presentation, while antibody tion) and dopamine transporter SPECT. Dopamine studies were pending, the patient developed painful transporter SPECT measures dopamine uptake in the left leg cramps, fixed left ankle dorsiflexion, and basal ganglia and is abnormal in neurodegenerative pronounced neck stiffness. EMG of the left leg parkinsonian disorders such as PD, MSA, CBS, and demonstrated continuous motor unit activity in the PSP, but cannot distinguish among them. left medial gastrocnemius, peroneus longus, and To evaluate for autoimmune or paraneoplastic vastus medialis. cerebellar degeneration, the patient had CSF studies Question for consideration: sent along with serum and CSF antineuronal antibodies and underwent PET/CT of the body to 1. What is the patient’s diagnosis? GO TO SECTION 5 Neurology 89 November 21, 2017 e249 ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. SECTION 5 cerebellar ataxia. Individuals with GAD65- Our patient’s worsening axial and limb stiffness and associated cerebellar ataxia can also have multifocal EMG are suggestive of stiff-person syndrome (SPS). neurologic symptoms, including brainstem dysfunc- Patients with SPS classically present with symmetric, tion, parkinsonism, or other movement disorders. board-like stiffness of axial and limb musculature, as Roughly 25% of GAD65 antibody-positive individu- well as painful muscle spasms that can be precipitated als with these multifocal extrapyramidal symptoms by startle. However, limited and asymmetric forms of also have limited SPS.4 SPS, such as stiff-limb or stiff-trunk syndrome, also Taken together, our patient’s cerebellar ataxia, exist. EMG in patients with SPS demonstrates the parkinsonian freezing of gait, neck and left leg stiff- electrophysiologic correlate of muscle spasm: contin- ness, and elevated anti-GAD65 titer suggest a diag- uous motor activity of opposing muscle groups. Lab- nosis of limited SPS (stiff-limb syndrome) in the oratory testing often reveals elevated anti-GAD65 context of multifocal GAD65 autoimmune neuro- antibodies. Our patient’s GAD65 antibody returned logic disease. positive at 113 nmol/L in the serum (normal ,0.02 nmol/L) and 16.4 nmol/L in the CSF. Question for consideration: Notably, GAD65 antibodies are not only associ- ated with SPS, but can also be associated with 1. How would you treat the patient? GO TO SECTION 6 e250 Neurology 89 November 21, 2017 ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. SECTION 6 Antibodies to GAD65 are common. They are pres- Treatment of SPS involves immunomodulatory and ent in 8% of the general population8 and are fre- symptomatic therapy. quently present in individuals with type I diabetes, Immunomodulation is more effective when initi- thyroid disease, and pernicious anemia. They are rarely ated early5 and should be considered before antibody associated with neurologic disease: SPS is the most tests return if SPS is highly suspected. Monthly IV common GAD65 antibody-associated neurologic dis- immunoglobulin (IVIg) is standard of care for SPS,6 ease, and prevalence is estimated at 1:1,250,000.9 though azathioprine, mycophenolate, or methotrex- It is important to note that when GAD65 anti- ate have been used as IVIg-sparing maintenance ther- bodies are associated with neurologic disease, serum apies. Rituximab and cyclophosphamide have been titers are markedly high—often above 100 nmol/L used for refractory cases.5 (reference ,0.02 nmol/L). Antibodies are often also Symptomatic treatment of SPS includes baclofen, ti- present in