Intracranial calcifications are associated with a variety of disorders, but marked pontine calcification without an underlying structural lesion has rarely been reported. Here we present a unique case with progressive ataxia palatal tremor (PAPT) associated with marked pontine calcification. A previously healthy 53-year old woman first noticed balance problems, slurred speech, and a constant oculopalatal tremor at age 48. Within 4 years of symptom onset, she progressed to requiring support when walking, developed swallowing difficulties, and intermittently had double incontinence. Cognition was intact. Medical history included type 2 diabetes (dietary management only), hypothyroidism (euthyroid for more than a decade), hypercholesterolemia, and arterial hypertension. She was taking lisinopril, simvastatin, levothyroxine, and fluoxetine. There was no family history of any neurological disorder.
On examination at age 52, she had cerebellar dysarthria and a synchronous ocular-facial-palatal myoclonus. She had titubatory head tremor and torticollis to the left. Examination of extraocular movements showed an elliptical ocular tremor synchronous with the palatal tremor, left lateral rectus palsy, and slow horizontal saccades but normal conjugate vertical eye movements and convergence. She had bilateral gaze-evoked nystagmus and finger–nose ataxia. Her gait was ataxic, requiring the support of 2 people in order to walk (Video 1). Sensation, power, and reflexes were normal. Follow-up at age 53 showed further deterioration of her dysarthria and gait. She is currently wheelchair bound (Video 2).
Routine blood tests including thyroid function, parathyroid hormone, lupus anticoagulant, white cell enzymes, cholestanol, very long chain fatty acids, and a blood film for acanthocytes were normal. Antinuclear, anti–neutrophil cytoplasmic, voltage-gated potassium channels, anti–glutamic acid decarboxylase, and anti–tissue transglutaminase antibodies were negative. Gastrointestinal biopsy excluded Whipple's and celiac diseases. Genetic tests for Alexander's disease (GFAP mutations ), spinocerebellar ataxias (SCA 1–6, 12, 17), fragile X–associated tremor ataxia syndrome, common mitochondrial mutations, and polymerase gamma mutations were negative. Cerebrospinal fluid examination showed no abnormalities. MRI showed a paired symmetrical low signal in the posterior aspect of the basis pontis and tegmentum on T2 (Fig. 1A), T1 (Fig. 1B), and FLAIR sequences and cerebellar, pontine, middle cerebellar, and cerebral peduncular volume loss. The low-signal region was confirmed to be calcification on a nonenhanced computerized tomography (CT) scan (Fig. 1C) that also demonstrated some patchy calcification within the rostral medulla. MR angiography and dopamine transporter imaging (DaTSCAN) were normal.
A causative relationship between the calcification and the clinical picture cannot be proven, as also is the case in other disorders with brain calcifications such as Fahr's disease. However, the association of the calcification with the patient's clinical picture is highly likely for many reasons. First, the localization of the calcification cannot be physiologic or incidental, as physiologic or incidental intracranial calcifications are by definition not accompanied by relevant signs and have a different distribution in CT that never involves isolated the pons, particularly to that degree. Second, the localization of the calcification is in keeping with the proposed pathomechanism of PAPT, namely, a lesion involving the Guillan-Mollaret triangle,[2, 3] causing an interruption of the inhibitory pathway from the dentate nucleus to the contralateral inferior olivary nucleus via the superior cerebellar peduncle and central tegmental tract.
In terms of possible underlying etiology, marked pontine calcification is described typically secondary to tumors or arteriovenous malformations[1, 4-6] or postirradiation, whereas rarer causes such as Krabbe disease and cerebrotendinous xanthomatosis were excluded in our patient. There is one case with a similar CT finding reported, but the clinical presentation was different, and the putative diagnosis was multiple system atrophy. However, no DaTSCAN was performed, and the diagnosis remained inconclusive. In our patient this possibility was excluded phenotypically but also by the normal DaTSCAN.
More widespread abnormal intracranial calcifications in adults can be part of an underlying systemic (eg, hypoparathyroidism, pseudo-hypoparathyroidism, pseudo-pseudohypoparathyroidism, hyperparathyroidism, systemic lupus erythematosus),[9, 10] neurodegenerative (eg, Fahr's disease, diffuse neurofibrillary tangles with calcification),[11, 12] or mitochondrial disorders (eg, myoclonic epilepsy with ragged red fibers, mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), but these conditions were excluded in our patient. Moreover, the calcification in these disorders typically shows a characteristic symmetric striato-pallido-dentate distribution. The brainstem can rarely be involved but is never the predominant localization of the calcification.[5, 13]
Further recognized causes of a PAPT syndrome such as GFAP mutations[14, 15] and celiac disease were excluded in our patient, whereas SCA20 is unlikely in our patient, as there was no family history, and imaging in SCA20 shows isolated dentate calcification (“dark dentate disease”).
We have described a novel case with marked pontine calcification in the context of PAPT syndrome. The diagnosis of this patient remains inconclusive and is only likely to be obtained at autopsy. We encourage others to report similar cases, as progressive ataxia with or without palatal tremor associated with marked pontine calcification may constitute a novel entity.
Video. Segment 1 shows the patient at age 52, 4 years after disease onset. She has synchronous oculopalatal tremor, also with synchronous movements of facial muscles and the right arm. She has a titubatory tremor of the head. She has cerebellar dysarthria and finger–nose ataxia. There is no bradykinesia. She has marked gait ataxia and can stand only with the help of another. Segment 2 shows the patient a year later with worsened dysarthria, head titubation, and finger–nose ataxia more in the right than the left. The patient cannot stand even with help of 2 others and is wheelchair bound.